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WO2010056795A1 - Nouveaux analogues synthétiques de dinucléoside polyphosphate et leur utilisation comme nouvelles modalités thérapeutiques et/ou diagnostiques - Google Patents

Nouveaux analogues synthétiques de dinucléoside polyphosphate et leur utilisation comme nouvelles modalités thérapeutiques et/ou diagnostiques Download PDF

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WO2010056795A1
WO2010056795A1 PCT/US2009/064114 US2009064114W WO2010056795A1 WO 2010056795 A1 WO2010056795 A1 WO 2010056795A1 US 2009064114 W US2009064114 W US 2009064114W WO 2010056795 A1 WO2010056795 A1 WO 2010056795A1
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analogs
ribose
guranowski
divalent
compound
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David Tabatadze
Paul C. Zamecnik
Andrzej Guranowski
Malay K. Raychowdhury
Michael G. Blackburn
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ZATA PHARMACEUTICALS Inc
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ZATA PHARMACEUTICALS Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Definitions

  • the invention relates to synthetic dinucleoside polyphosphate analogs and their use as therapeutic compounds and/or diagnostic tools for the treatment and diagnosis of various human diseases and metabolic disorders.
  • Diadenosine polyphosphates are members of a group of dinucleoside polyphosphates that are widely present in eukaryotic cells and play vital roles in their metabolism [Garrison
  • Diadenosine polyphosphates have been identified as modulators of cardiovascular and neurotransmitter- like activities in addition to their previously described role in cell proliferation and as signal molecules when cells are undergoing stress [Baxi et al. 1995].
  • the wide abundance of dinucleoside polyphosphates in almost all types of eukaryotic cells makes their synthetic analogs potentially promising as therapeutic and diagnostic modalities.
  • Several synthetic analogs of diadenosine polyphosphates have been tested successfully as potential therapeutic and diagnostic tools [Holler et al. 1983, Zamecnik et al. 1992, Chan et al. 1997, Elmaleh et al. 1998, Elmaleh
  • the present invention identifies new synthetic dinucleoside polyphosphate analogs and their use as therapeutic agents and/or diagnostic tools.
  • the invention provides compounds having structural formula I:
  • X and X' are nucleosides or modified nucleoside groups, deoxynucleoside groups or seconucleoside groups each independently selected from adenosin-5'-yl cytidin-5'-yl, 2,6- diaminopurineribosyl-5'-yl, inosin-5'-yl, guanosin-5'-yl, thymidin-5'-yl, uridin-5'-yl, ethenoadenosin-5'-yl, or other heterocyclic, cyclic or non-cyclic chemical groups attached to a sugar selected from D-ribose, 2-deoxy-D-ribose, 2,3-dideoxy-D-ribose, morpholino-, 2- and/or 3-OMe-ribose, 2- and/or 3-OEt-ribose, 2- and/or 3 -F, -Br, -Cl, -N 3 2- and/or
  • each B is independently selected from -O , -S " , -NH 3 + , short alkyl, and other charged or neutral chemical groups bonded to the phosphorus atom by a single covalent bond.
  • Each of Y 1 , Y 2 , Y 3 is separately selected from -O-, -S-, -NH-, -C(O)-CH 2 -, -CH 2 -CO-, monohalomethylene, dihalomethylene, carboxymethylene, alkylcarboxymethylene, aralkylcarboxymethylene, phosphonomethylene, sulfonomethylene, 1 ,2-ethylene, 1,1 -ethylene, 1,1 -propylene, 1 ,2-propylene, oxy(halo)methylene, halomethyleneoxy, thiomethylene, thiomethyleneoxy, and other linear and other divalent atoms charged or neutral divalent chemical groups serving as a bridge between two adjacent phosphorus atoms, k, 1, m, and n are integral numbers from 0 to 5; where the sum of (k+l+m+n) is ⁇ 2 and ⁇ 7.
  • the invention provides a pharmaceutical formulation comprising a compound according to the invention and a pharmaceutically acceptable diluent, carrier or excipient.
  • the invention provides a diagnostic method for detecting atherosclerotic lesions.
  • the method according to this aspect of the invention comprises administering to a patient suspected of having an atherosclerotic lesion a labeled compound according to the invention, allowing the labeled compound to bind to the atherosclerotic lesion and detecting the labeled compound at the site of the atherosclerotic lesion.
  • the invention provides a therapeutic method for treating a disease or disorder associated with blood disorders.
  • the method according to this aspect of the invention comprises administering to a patient having a blood disorder or a disease associated with a blood disorder a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.
  • the invention provides a method for modulating an enzyme activity.
  • the method according to this aspect of the invention comprises contacting a cell containing an enzyme with a compound according to the invention.
  • the cell is in a mammal, such as a human.
  • the compounds according to the invention are useful as primary phosphoryl energy donors, as agonists or antagonists of specific metabolic signaling pathways, as in toto effector molecules and as precursors of cyclic AMP, cyclic GMP, cyclic CMP, cyclic UMP, cyclic TMP, and other similar cyclic phosphate modifications of altered nucleoside bases of A, C, G, U and T.
  • cyclic AMP cyclic GMP
  • cyclic CMP cyclic CMP
  • cyclic UMP cyclic TMP
  • other similar cyclic phosphate modifications of altered nucleoside bases of A, C, G, U and T are useful as analogs of the bodily compounds (Np n N) compared with other synthetic therapeutics.
  • the potential products of degradation of the dinucleoside polyphosphate analogs will also be analogs of bodily compounds and as such are expected to have minimal undesirable side effects.
  • Figure 1 shows time course of AdOOpOpCH 2 OpOpOAdO hydrolysis catalyzed by narrow-leaved lupin Ap 4 A hydrolase monitored by (a) HPLC and (b) chromatography of standard nucleotides.
  • Figure 2 shows a comparison of binding and modes of reactivity of dinucleotides 3, 4, and 5 by the asymmetrically-acting Ap 4 A hydrolases, (a) Major cleavage of 3 to ⁇ , ⁇ - methyleneoxy-ATP; (b) minor cleavage of 3 to ⁇ , ⁇ -oxymethylene-ATP; (c) frame-shift cleavage of 5 to ⁇ , ⁇ -oxymethylene-ADP; (d) stability to frame-shift cleavage of 4.
  • the invention relates to novel synthetic dinucleoside polyphosphate analogs and their use as therapeutic compounds and/or diagnostic tools for the treatment and diagnosis of various human diseases and metabolic disorders.
  • the references cited herein reflect present knowledge in the art, and are hereby incorporated by reference in their entirety. Any conflicts between the cited references and this specification shall be resolved in favor of the latter.
  • the invention provides compounds having structural formula I
  • X and X' are nucleosides or modified nucleoside groups, deoxynucleoside groups or seconucleoside groups each independently selected from adenosin-5'-yl cytidin-5'-yl, 2,6- diaminopurineribosyl-5'-yl, inosin-5'-yl, guanosin-5'-yl, thymidin-5'-yl, uridin-5'-yl, ethenoadenosin-5'-yl, or other heterocyclic, cyclic or non-cyclic chemical groups attached to a sugar selected from D-ribose, 2-deoxy-D-ribose, 2,3-dideoxy-D-ribose, morpholino-, 2- and/or 3-OMe-ribose, 2- and/or 3-OEt-ribose, 2- and/or 3 -F, -Br, -Cl, -N 3 2- and/or
  • each B is independently selected from -O " , -S " , -NH 3 + , short alkyl, and other charged or neutral chemical groups bonded to the phosphorus atom by a single covalent bond.
  • Each of Y 1 , Y 2 , Y 3 is separately selected from monohalomethylene, dihalomethylene, carboxymethylene, alkylcarboxymethylene, aralkylcarboxymethylene, phosphonomethylene, sulfonomethylene, 1 ,2-ethylene, 1,1 -ethylene, 1,1 -propylene, 1 ,2-propylene, oxy(halo)methylene, halomethyleneoxy, thiomethylene, thiomethyleneoxy, and other linear and other divalent atoms charged or neutral divalent chemical groups serving as a bridge between two adjacent phosphorus atoms, k, 1, m, and n are integral numbers from 0 to 5; where the sum of (k+l+m+n) is > 2 and ⁇ 7.
  • the compounds according to the invention have a structure selected from
  • two X moieties can be the same or different nucleoside groups or nucleoside analog groups.
  • the compounds according to the invention are abbreviated herein as having the structures
  • the present invention also includes pharmaceutically acceptable salts and prodrugs of compounds of the invention.
  • prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient when the prodrug is administered to a mammalian subject, or to a fungal cell. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of compounds of the invention include compounds wherein a hydroxy, amino, carboxylic, phosphate, or a similar group is modified.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups, amides (e.g., trifluoroacetylamino, acetylamino, and the like), phosphonamides (e.g. phosphonamides from natural and non-natural ⁇ -amino acid esters) and the like.
  • the invention provides a pharmaceutical formulation comprising a compound according to the invention and a pharmaceutically acceptable diluents, carrier or excipient.
  • compositions according to the invention may contain, in addition to the inhibitor and antifungal agent, diluents, excipients, fillers, salts, buffers, stabilizers, solubilizers, and/or other materials well known in the art.
  • diluents e.g., The Science and Practice of Pharmacy, 20 th Edition, ed. A. R. Gennario, Lippincott, Williams, and Watkins, Baltimore, MD, 2000.
  • salts include, but are not limited to acid addition salts formed with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, benzenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, algin
  • the compounds can also be in the form of pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR 3 + + Z " , wherein R is hydrogen, alkyl, or benzyl, and Z is a counter anion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, phenylacetate, and diphenylacetate).
  • salt is also meant to encompass complexes, such as with an alkaline metal or an alkaline earth metal.
  • the active compounds of a composition of the invention are included in the pharmaceutically acceptable carrier in an amount sufficient to deliver an effective desired amount without causing serious toxic effects to an individual to which the composition is administered.
  • the invention provides a diagnostic method for detecting atherosclerotic lesions.
  • the method according to this aspect of the invention comprises administering to a patient suspected of having an atherosclerotic lesion a labeled compound according to the invention, allowing the labeled compound to bind to the atherosclerotic lesion and detecting the labeled compound at the site of the atherosclerotic lesion.
  • the compounds according to the invention provide the possibility of higher specific labeling and detection of atherosclerotic lesions, with earlier recognition of such damage in arteries of the cardiac, cerebral, renal, and other circulatory pathways.
  • the compounds are labeled either fluorescently or radioactively.
  • the invention provides a therapeutic method for treating a disease or disorder associated with blood disorders.
  • the method according to this aspect of the invention comprises administering to a patient having a blood disorder or a disease associated with a blood disorder a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.
  • ADP adenosine diphosphate
  • an effective amount is an amount of a compound of the invention that achieves the effect which is intended with its application.
  • the amount of a compound of the invention which constitutes an “effective amount” will vary depending on the compound, the intended use, the disease state and its severity, the age of the patient to be treated, and the like. The effective amount can be determined routinely by one of ordinary skill in the art.
  • patient as employed herein for the purposes of the present invention includes humans and other animals, particularly mammals.
  • the compounds, compositions and methods of the present invention are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in a most preferred embodiment the patient is human.
  • treating covers the treatment of a disease or disorder in an animal, preferably a mammal, including a human, and includes at least one of: (i) preventing the disease-state from occurring in the animal, in particular, when such animal is predisposed to the disease or disorder but has not yet been diagnosed as having it; (ii) inhibiting the disease or disorder, i.e. arresting its development; and (iii) relieving the disease or disorder, i.e. causing regression of the disease or disorder.
  • Preferred diseases or disorders include, without limitation, hemophilia, thromboses, leukemia, multiple myeloma, malignant melanoma, and other forms of cancer.
  • Administration of the compounds or formulations according to the invention may be administered by any suitable route, including, without limitation, parenterally, intravenously, or by local implantation or inhalation.
  • the invention provides a method for modulating an enzyme activity.
  • the method according to this aspect of the invention comprises contacting a cell containing an enzyme with a compound according to the invention.
  • the cell is in a mammal, such as a human.
  • the invention provides novel diadenosine polyphosphate analogs with oxymethylene bridges replacing one or more interphosphorus oxygens in the polyphosphate chain (compounds 1-6).
  • the invention also provides six other novel compositions, in which the interphosphorus oxygen in polyphosphates of diadenosine polyphosphates are replaced with -CHF-, -CH(COOH)-, - CH(CO 2 CH 2 Ph)-; -CCl(PO 3 H 2 )- , -CH 2 - chemical groups (Compounds 37-44), as well as novel compounds 43-48 with modifications at internucleoside phosphates and the adenosin- 5'-yl moiety or an analog thereof
  • the compounds according to the invention may serve as traffic signals, with a green light opening avenues to rich metabolic areas. They may act as agonists or antagonists of specific metabolic signaling pathways or may substitute for nucleoside di-, tri-, tetra- and higher poly-phosphates, as primary phosphoryl energy donors, in specific signal transduction pathways dictated by the structural features of enzymatic catalysts.
  • Np n N' analogs One of the most successful approaches to understanding their biological functions has been the use OfNp n N' analogs.
  • novel diadenosine polyphosphate analogs having an oxymethylene group replacing one or two bridging oxygen(s) in the polyphosphate chain. These have been tested as potential substrates and/or inhibitors of the symmetrically-acting Ap 4 A hydrolase (EC 3.6.1.41) from E. coli and of two asymmetrically-acting Ap 4 A hydrolases (EC 3.6.1.17) from humans and narrow-leaved lupin.
  • tripolyphosphate analog -pOCH2pCH2Op-
  • AP 3 A The tripolyphosphate analog, -pOCH2pCH2Op-
  • hitherto similar analogs OfAp 4 A or Ap 5 A have not been made.
  • Example 1 AdoOpCH 2 OpOCH 2 pOAdo (1) Monobenzyl phosphonate 8 [Rejman et al. 2006] was esterif ⁇ ed with tetrabenzoyladenosine 7 [Rejman et al. 2006] using either 2- chloro-5,5-dimethyl-2-oxido-l,3,2-dioxaphosphinane (NEP)/methoxypyridine- ⁇ /- oxide/pyridine system [Himmelsbach et al. 1984, Stengele et al.
  • Target compound 1 was obtained by two-step deprotection and DEAE Sephadex column chromatography using a linear gradient of TEAB in water. Benzyl esters were removed by catalytic hydrogenation followed by aqueous ammonia treatment to remove benzoyl protecting groups.
  • Example 2 AdoOpOCH 2 pCH 2 OpOAdo (2) Tetrabenzoyladenosine 7 was converted into phosphoramidite 12 by reaction with benzyloxybis(diisopropylamino)phosphine [Bannwarth et al. 1987] (Scheme 2). Phosphoramidite 12 underwent reaction with benzyl bis(hydroxymethane)phosphinate 13 providing fully protected symmetrical Ap 3 A analog 14. Final compound 2 was obtained by two-step deprotection and DEAE Sephadex column chromatography using a linear gradient of TEAB in water.
  • Example 3 AdoOpOpCH 2 OpOpOAdo (3)
  • the tributylammonium salt of AMP (15) was reacted with phosphomorpholidate 16 in DMSO.
  • Dibenzyl ester 17 was hydrogenolyzed to give ATP analog 18, purified by DEAE-Sephadex chromatography.
  • Reaction of 18 with AMP morpholidate 19 led to target product 3 after DEAE Sephadex column chromatography, using a linear gradient of TEAB in water.
  • Example 4 AdoOpCH 2 OpOpOCH 2 pOAdo (4) Adenosine phosphonate 10 (vs.) was reacted with bis-benzyloxy-(diisopropylamino)phosphine [Bannwarth et al. 1987] with tetrazole catalysis and, after MCPBA oxidation, afforded compound 20 (Scheme 4). Compound 20 was debenzylated by catalytic hydrogenolysis and dimerized using DCC in pyridine. Target compound 4 was obtained pure by DEAE Sephadex column chromatography.
  • Example 5 AdOOpOCH 2 POpCH 2 OpOAdO (5) Phosphoramidite 12 was reacted with dibenzyl phosphonate 22 using tetrazole catalysis and, after MCPBA oxidation, afforded compound 23 (Scheme 6).
  • Example 7 pOCH 2 pOpOAdo (32) Bis(2-cyanoethyloxy)(diisopropylamino)- -phosphine (27) [Bannwarth and Trquelak, 1987] was reacted with dibenzyl phosphonate 22 and subsequently with benzyl alcohol. After MCPBA oxidation and catalytic hydrogenation cyanoethyl pyrophosphate analog 30 was obtained (Scheme 7). Pyrophosphate analog 30 underwent standard reaction with adenosine 5'-phosphoromorpholidate 19. After aqueous ammonia deprotection of the cyanoethyl group and DEAE Sephadex column purification, the target ATP analog 32 was obtained.
  • Bis(hydroxymethane)phosphinic acid 33 [Pirat et al. 2002] was reacted with dimethoxytrityl chloride in pyridine to give 34, which was subsequently esterified with benzyl alcohol employing NEP/methoxypyridine-N -oxide/pyridine system [Himmelsbach et al. 1984, Stengele et al. 1990, Rejman et al. 2004]. The benzyl ester 35 obtained was detritylated with
  • Morpholinophosphonic dichloride 36 [Nunez et al. 1987] was treated first with one equivalent of water in pyridine to afford a reactive species that subsequently underwent reaction with dibenzyl hydroxymethanephosphinate 24 to afford the desired reagent 16.
  • AdoOpOpCH 2 pOpOAdo and AdoOpCH 2 pOpOAdo were hydrolyzed 20- to 50-fold more slowly and AdoOpOpCF 2 pOpOAdo, AdoOpOpCHFpOpOAdo, AdoOpOpCHBrpOpOAdo and AdoOpOpCHClpOpOAdo 1.4- to 9-fold more slowly than Ap 4 A.
  • AdoOpOpCHFpOpOAdo AdoOpOpCHBrpOpOAdo
  • AdoOpOpCHClpOpOAdo 1.4- to 9-fold more slowly than Ap 4 A.
  • their efficiencies as substrates of the Ap 4 A hydrolase from Artemia increased in direct proportion to increasing electronegativity [McLennan et al. 1989]. Guranowski et al.
  • asymmetric analog 3 was hydrolyzed by both asymmetric hydrolases to AMP and the ⁇ , ⁇ -methyleneoxy-ATP (32) (Fig. 2a), and then the latter, relatively unstable, nucleotide more slowly cleaved spontaneously to give a second AMP.
  • Profiles shown in Fig. Ia are for reaction mixtures (0.1 ml) containing 50 mM Hepes/KOH (pH 7.6), 0.02 mM dithiothreitol, 5 mM MgCl 2 , 0.5 mM substrate, and rate- limiting amounts of the asymmetrically acting Ap 4 A hydrolase - incubated at 30 0 C. At time intervals (0, 5, 10, 15 and 20 min), 10 ⁇ l aliquots were withdrawn, added to 0.15 ml of 0.1 M KH 2 PO 4 (pH 6.0) and the reaction heat-quenched (3 min at 96°C).
  • Guranowski A Galbas M, Hartmann R, Justesen, J. (2000) Selective degradation of 2'- adenylated diadenosine tri- and tetraphosphates, Ap 3 A and Ap 4 A, by two specific human dinucleoside polyphosphate hydrolases, Arch. Biochem. Biophys. 373: pp 218-224. Guranowski A. (2003) Analogs of diadenosine tetraphosphate (Ap 4 A). Acta Biochim. Polon. 50: pp 947-972.
  • Uridine 5'- polyphosphates p 4 U and P 5 U
  • uridine (5')polyphospho(5')nucleosides Up n Ns
  • UTP glucose- 1 -phosphate uridylyltransferase from Saccharomyces cerevisiae.
  • FEBS Lett. 561 pp 83-88.
  • McLennan AG Taylor GE, Prescott M, Blackburn, GM. (1989) Recognition of ⁇ , ⁇ '- substituted and ⁇ , ⁇ ; ⁇ ', ⁇ '-disubstituted phosphonate analogs of bis(5'-adenosyl) tetraphosphate by the bis(5'-nucleosidyl)-tetraphosphate pyrophosphohydrolases from Artemia embryos and Escherichia coli. Biochemistry 28: pp 3868-3875. McLennan AG. (2000) Dinucleoside polyphosphates - friend or foe? Pharmacol. Ther. 87: pp 73-89.

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Abstract

La présente invention concerne de nouveaux analogues synthétiques de dinucléoside polyphosphate et leur utilisation comme composés thérapeutiques et/ou outils diagnostiques dans le traitement et le diagnostic de diverses maladies et divers troubles métaboliques humains.
PCT/US2009/064114 2008-11-12 2009-11-12 Nouveaux analogues synthétiques de dinucléoside polyphosphate et leur utilisation comme nouvelles modalités thérapeutiques et/ou diagnostiques Ceased WO2010056795A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575127B2 (en) 2008-11-20 2013-11-05 Glsynthesis Inc. Antithrombotic diadenosine tetraphosphates and related analogs
KR20190012388A (ko) * 2017-07-27 2019-02-11 (주)리독스바이오 디(뉴클레오시드 5'-)폴리포스페이트의 제조 방법
CN113999270A (zh) * 2021-11-30 2022-02-01 新乡拓新药业股份有限公司 一种合成胞苷二磷酸的方法
WO2025144919A1 (fr) * 2023-12-28 2025-07-03 Zata Pharmaceuticals, Inc. Procédés et compositions pour l'administration orale, sublinguale ou buccale d'analogues de diadénosine tétraphosphate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6299857B1 (en) * 1995-12-28 2001-10-09 The General Hospital Corporation Cardiovascular and thrombus imaging agents, methods and kits
US20040220133A1 (en) * 2000-08-21 2004-11-04 Boyer Jose L. Composition and method for inhibiting platelet aggregation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6299857B1 (en) * 1995-12-28 2001-10-09 The General Hospital Corporation Cardiovascular and thrombus imaging agents, methods and kits
US20040220133A1 (en) * 2000-08-21 2004-11-04 Boyer Jose L. Composition and method for inhibiting platelet aggregation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575127B2 (en) 2008-11-20 2013-11-05 Glsynthesis Inc. Antithrombotic diadenosine tetraphosphates and related analogs
KR20190012388A (ko) * 2017-07-27 2019-02-11 (주)리독스바이오 디(뉴클레오시드 5'-)폴리포스페이트의 제조 방법
KR101985791B1 (ko) 2017-07-27 2019-06-05 (주)리독스바이오 디(뉴클레오시드 5'-)폴리포스페이트의 제조 방법
CN113999270A (zh) * 2021-11-30 2022-02-01 新乡拓新药业股份有限公司 一种合成胞苷二磷酸的方法
CN113999270B (zh) * 2021-11-30 2023-03-14 新乡拓新药业股份有限公司 一种合成胞苷二磷酸的方法
WO2025144919A1 (fr) * 2023-12-28 2025-07-03 Zata Pharmaceuticals, Inc. Procédés et compositions pour l'administration orale, sublinguale ou buccale d'analogues de diadénosine tétraphosphate

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