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WO1999003480A1 - Utilisation d'adenosine tri- ou tetra-phosphates et de leurs analogues dans le traitement de l'infarctus cerebral - Google Patents

Utilisation d'adenosine tri- ou tetra-phosphates et de leurs analogues dans le traitement de l'infarctus cerebral Download PDF

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Publication number
WO1999003480A1
WO1999003480A1 PCT/GB1998/002101 GB9802101W WO9903480A1 WO 1999003480 A1 WO1999003480 A1 WO 1999003480A1 GB 9802101 W GB9802101 W GB 9802101W WO 9903480 A1 WO9903480 A1 WO 9903480A1
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WO
WIPO (PCT)
Prior art keywords
reperfusion
same
group
different
infarction
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PCT/GB1998/002101
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English (en)
Inventor
Christoph Thiemermann
Jun Wang
Original Assignee
William Harvey Research Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GB9715198A external-priority patent/GB9715198D0/en
Priority claimed from GBGB9719596.0A external-priority patent/GB9719596D0/en
Application filed by William Harvey Research Limited filed Critical William Harvey Research Limited
Priority to AU83514/98A priority Critical patent/AU8351498A/en
Publication of WO1999003480A1 publication Critical patent/WO1999003480A1/fr

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Classifications

    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

Definitions

  • the present invention relates to compounds for use in the 5 treatment or prophylaxis of infarction associated with reperfusion injury, particularly cerebral infarction associated with reperfusion injury.
  • Infarction is most commonly due to the blockage of a 0 nutritive blood vessel to the tissue or organ by a blood clot or thrombosis.
  • the subsequent cessation of blood flow (ischae ia) to the tissue or organ results in the death of some of the tissue or organ.
  • reperfusion-induced arrhythmias include (i) reperfusion-induced arrhythmias, (ii) myocardial stunning (iii) lethal reperfusion injury and (iv) accelerated necrosis.
  • reperfusion-induced arrhythmias include (i) reperfusion-induced arrhythmias, (ii) myocardial stunning (iii) lethal reperfusion injury and (iv) accelerated necrosis.
  • alterations in calcium- homeostasis occur much more frequently during the reperfusion of the ischaemic myocardium.
  • Oxygen-derived free radicals (superoxide anions, hydroxyl-radical, hydrogen peroxide) are generated upon reperfusion and cause increased membrane permeability.
  • the increased membrane permeability allows easier access of calcium into the myocytes leading to mitochondrial calcium overload with subsequent damage to the mitochondrial structure and loss of the ability to produce adenosine triphosphate (ATP) , which ultimately results in cell death.
  • ATP adenosine triphosphate
  • myocardial ischaemia which as a condition is distinct from cerebral ischaemia, reperfusion injury and especially cerebral reperfusion injury.
  • myocardial ischaemia describes a condition that exists when the uptake of oxygen in the heart is insufficient to maintain the rate of cellular oxidation and metabolism. This leads to extremely complex situations, which have been extensively studied in recent years.
  • drugs which reduce infarct size when given during the ischaemic period are likely to give protection by causing a reduction in ischaemic tissue injury. This applies particularly to drugs which are rapidly metabolised, as they are unlikely to interfere with the consequences of reperfusion.
  • Diadenosine 5' , 5' ' '-P',P 4 -tetraphosphate has been reported (European Patent Application EP-A2-0437929) as being useful in the treatment of heart disease, specifically in the treatment of arryth ia or for use as a vasodilator.
  • Use of diadenosine 5 ' , 5 ' ' '-P 1 , P 4 -tetraphosphate as an anti- thrombotic agent is also discussed in International Patent Application WO89/04321 and United States Patent 5,049,550.
  • Diadenosine 5 ' , 5 ' ' ' -P' , P pentaphosphate has been reported to be an inhibitor of adenylate kinase (G.E. Lienhard et al . , J. Biol. Chem. , 248, 1121 (1973); S.M. Humphrey et al . , Journal of Surgical Research, 43, 1987)).
  • diadenosine 5' , 5' ' '-P 1 , P 4 -tetraphosphate for curing ischaemic myocardial disease is disclosed in European Patent Application EP-A1-0689838. No reference to cerebral ischaemia or reperfusion injury or the reduction of cerebral infarction is made in the application.
  • analogues of 5 ' , 5 ' ' ' -P 1 , P 4 tetraphosphate have been disclosed in the prior art (Blackburn et al . , NAR 15, 6994- 7025, (1987)) as well as a number of analogues of 5', 5"'- P',P 3 -triphosphate (AP 3 A) (Blackburn et al . , Tetrahedron letters, 31, 5637-5640, (1990) and Guranowski et al . , Nucleosides and Nucleotides, 14, 731-734, (1995)).
  • the analogues may be useful in the treatment or prophylaxis of cerebral infarction associated with ischaemia and/or reperfusion injury.
  • X 1 and X 2 may be the same or different and each is a substituted, unsubstituted or modified purine base
  • each group represented by Y may be the same or different and each is selected from the group comprising -0- and -CZ'z 2 -
  • Z 1 and Z 2 may be the same or different and each is selected from the group comprising hydrogen, halogen and alkyl groups
  • each atom represented by W may be the same or different and each is selected from the group comprising oxygen and sulfur
  • n is 2 or 3, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of cerebral infarction associated with reperfusion injury.
  • Infarction associated reperfusion injury is defined as the tissue necrosis or damage caused on reperfusion of an ischaemic tissue and does not include ischaemic tissue damage, namely that caused by the cessation of blood flow to the tissue.
  • X 1 and X 2 may be the same or different. Preferably X 1 and X 2 are the same.
  • X 1 and X 2 may comprise a substituted, unsubstituted or modified purine base or derivative thereof.
  • X 1 and X 2 comprise adenine or a derivative thereof, or guanine or a derivative thereof.
  • X 1 and X 2 comprise adenine or guanine, more preferably adenine.
  • Adenine and derivatives thereof may comprise radicals of formula (II) : -
  • R 1 and R 2 may be the same or different and are selected from the group comprising hydrogen, halogen, and alkyl, aryl, alkoxy, aryloxy, alkythio and arylthio groups, and R 3 and R 4 are the same or different and are selected from the group comprising hydrogen and alkyl, aryl, alkanoyl and aroyl groups.
  • Adenine and derivatives thereof may also comprise isomers of the radicals of formula (II) , for example radicals of the formula (Ila) :-
  • Guanine and derivatives thereof comprise compounds of the formula (III) :-
  • R 1 , R and R 4 are as defined above, and R s is selected f-rom the groups comprising hydrogen and alkyl, aryl, alkanoyl and aroyl groups.
  • Guanine and derivatives thereof may also comprise isomers of the radicals of formula (III) , for example radicals of the formula (Illa):-
  • Modified purines include deazapurines.
  • modified purines include deazaadenine and derivatives thereof which comprise radicals of formula (IV):-
  • R 2 , R 3 and R 4 are as defined above, and the R 1 groups are independently selected from the definition of R 1 above.
  • Modified purines also include deazaguanine and derivatives thereof which comprise radicals of formula (V):-
  • R 2 , R 3 and R 4 are as defined above, and the R 1 groups are independently selected from the definition of R 1 above.
  • Qther modified purines which will be useful in the present invention will be apparent to those skilled in the art.
  • alkoxy and aryloxy groups means alkyl-O- and aryl-O- groups, and their haloalkyl-O- and haloaryl-O- groups, respectively.
  • Reference to alkanoyl and aroyl groups means alkyl-CO- and aryl-CO- , respectively.
  • Reference in the present specification to an alkyl group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C 3 to C 12 , more preferably C 5 to C 1() , more preferably C 5 to C 7 .
  • the alkyl group is preferably C, to C 10 , more preferably Cj to C 6 , more preferably methyl, ethyl, propyl or a halo-derivative thereof.
  • an aryl group means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl and thiophenyl.
  • the aryl group comprises phenyl.
  • the alkyl and aryl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include halogen atoms; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyloxy; nitrogen containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur containing groups such as thiol, alkythiol, sulphonyl and sulphoxide; heterocyclic groups containing one or more, preferably one, heteratom, such as thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidiny
  • halogen means a fluorine, chlorine, bromine or iodine radical, preferably fluorine or chlorine radical.
  • Each group represented by Y may be the same or different and each is selected from the group comprising -O- (oxygen) and -CZ'Z 2 - (substituted or unsubstituted methylene radicals) .
  • Y are not the same and preferably at least one is -O- and the other or others is/are CZ'Z 2 .
  • Each Y may comprise -CZ'z 2 - wherein Z 1 and Z 2 may be the same or different and each is selected from the group comprising hydrogen, halogen and alkyl groups.
  • -CZ'z 2 - is CC1 2 , CHC1, CF 2 , CHF or CH 2 .
  • Each atom represented by W may be the same or different and each is selected from the group comprising oxygen and sulfur.
  • W are the same and each are oxygen.
  • the compound for the use of the present invention is diadenosine 5 ' 5 ' ' ' ' -P 1 , P-substituted triphosphate or diadenosine 5' 5' ' '-P 1 , P 4 -substituted tetraphosphate, and more preferably APCC1 2 PCC1 2 PA, APCF 2 PCF 2 PA, APCHFPCHFPA, APCHC1PCHC1PA, APCH 2 PCH 2 PA, APCC1 2 PPCC1 2 PA, APCF 2 PPCF 2 PA, APCHFPPCHFPA, APCHClPPCHClPA or APCH 2 PPCH 2 PA.
  • Reference to cerebral infarction associated with reperfusion injury means tissue necrosis or damage to cerebral tissue arising from the reperfusion of ischaemic cerebral tissue with blood.
  • "Reperfusion injury” is thought to be due to the invasion of injured tissue with neutrophils (white blood cells) , which then become activated and cause the release of oxygen radicals and enzymes.
  • a particular feature of the present invention is the prophylactic protection of cerebral tissue afforded by the compounds of the invention against infarction associated with reperfusion injury. This feature makes the compounds of the invention particularly useful in the prophylaxis of infarction associated with reperfusion injury in conditions associated with interruption on the blood supply to cerebral tissue and subsequent reperfusion (for example, thrombosis, hypoperfusion due to surgery, trauma etc.).
  • the compounds of the present invention are also particularly useful in the prophylaxis of conditions of cerebral reperfusion such as stroke.
  • the medicaments employed in the present invention can be administered by oral or parenteral route, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol) , rectal and topical administration.
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl onostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • the compounds of the invention may also be presented as liposome formulations.
  • the compounds of the present invention may be presented alone or in combination with thrombolytic agents such as t- PA or streptokinase, or with agents such as prostacyclin, nitric oxide donors, organic nitrates, calcium antagonists, inhibitors of the activity of poly (ADP-ribose) synthetase (PARS) or nitric oxide synthase inhibitors.
  • thrombolytic agents such as t- PA or streptokinase
  • agents such as prostacyclin, nitric oxide donors, organic nitrates, calcium antagonists, inhibitors of the activity of poly (ADP-ribose) synthetase (PARS) or nitric oxide synthase inhibitors.
  • the invention further provides use of a compound of formula (I) or an analogue thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of inflammation associated with reperfusion injury of cerebral tissue.
  • a method of treatment or prophylaxis of cerebral tissue infarction or inflammation associated with reperfusion injury comprising adminstration to a patient, an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is APSPCC1 2 PA, APSPCF 2 PA, APSPCHC1PA or APSPCH 2 PA.
  • APSPCHC1PA has stereoisomeric centres at P and C in the phosphate moiety, which are marked with an asterisk in the formula below, and therefore has 4 stereoisomers for this phosphate moiety.
  • Figure 1 illustrates the effect of AP 4 A administered prior to onset of ischaemia on: (A) volume of cerebral infarction (expressed in mm 3 ) ; (B) area of largest infarction in one single brain slice (mm 2 ) ; (C) the number of infarcted slices per rat brain; and (D) the incidence of infarction within the whole group of animals tested.
  • Figure 2 illustrates the effect of AP 4 A administered prior to onset of ischemia and the effect of AP 4 A administered prior to onset of reperfusion on: (A) volume of cerebral infarction (expressed in mm 3 ) ; (B) area of largest infarction in one single brain slice (mm 2 ) ; (C) the number of infarcted slices per rat brain; and (D) the incidence of infarction within the whole group of animals tested.
  • Figure 3 illustrates the effects of adenosine administered prior to onset of reperfusion on: (A) volume of cerebral infarction (expressed in mm 3 ) ; (B) area of largest infarction in one single brain slice (mm 2 ) ; (C) the number of infarcted slices per rat brain; and (D) the incidence of infarction within the whole group of animals tested.
  • a total of 37 adult male Sprague-Dawlay rats (weight 375 ⁇ lOg) were used.
  • the animals were anaesthetised with chloral hydrate (400mg/kg, i.p.).
  • a compound of the invention or its vehicle phosphate-buffered saline
  • phosphate-buffered saline was injected into the left lateral cerebral ventricle at a volume of lO ⁇ l.
  • Ten minutes after this i.e. v. injection the squamosal bone overlying the right frontal and temporal cortex was removed (an area of approximately 2 x 2 mm 2 ) .
  • the right MCA was ligated with a 10-0 suture for ninety minutes.
  • a ninety minute ligation of this artery induces a maximal cerebral infarction in the rat (Du et al . , J Cereb Blood Flow Metab 16, 195-201 (1996)) .
  • the clip was removed to allow a subsequent twenty four hour reperfusion period. At the end of this reperfusion period, the animal was killed by an overdose of anaesthetic and then received an infusion of saline solution which was administered intracardially.
  • the brain was removed, immersed in cold saline for five minutes and sliced into 2 mm sections.
  • the brain slices were then incubated in a 2% tri-phenyl-tetrazoliun chloride (TTC) dissolved in phosphate buffered saline (thirty minutes at 37 'C) and then transferred to 5% formaldehyde solution for fixation (Chan et al . 1986) .
  • TTC tri-phenyl-tetrazoliun chloride
  • phosphate buffered saline phosphate buffered saline
  • formaldehyde solution formaldehyde solution for fixation
  • vehicle O.IM phosphate buffered saline, PBS
  • adenosine All animals randomised to this treatment received immediately prior to reperfusion a total dose of 2.5 ⁇ g of adenosine dissolved in 25 ⁇ l of 0.1M PBS: lO ⁇ l of this solution of adenosine (containing lO ⁇ g of the drug) were injected i.e.v., while three injections (5 ⁇ l each containing 5 ⁇ g of adenosine) were subsequently made directly into the cerebral cortex.
  • Adenosine 5'-P 1 ,P 2 -dichloromethylenebisphosphate was prepared from adenosine (as described in Davisson, V.J. et al . , J. Org. Chem. , 52, 1794-1801 (1987) for adenosine 5 ' - ,3-difluoromethylene-bisphosphate) but using dichloromethylenebisphosphonate in place of difluoro ethylenebisphosphonate. Yield 46 %.
  • ⁇ S H (D 2 0) 8.47 (s, H 8 ) , 7.95 (s, H 2 ),6.0 (d,
  • Adenosine 5 ' -thiophosphate (180 mg, 0.308 mmol) as its bis-triethylammonium salt and tri-n-octylamine (0.141 ml, 0.323 mmol) were shaken in methanol (7 ml) until dissolution was achieved. The solution was evaporated under reduced pressure. The residue was then coevaporated with pyridine (3 x 10 ml) and further dried under vacuum over P 2 0 5 for 12 h. The oily residue was then dissolved in dry dioxane (3 ml).
  • Adenosine 5'-(P 1 ,P 2 -dichloromethylene) diphosphate (165 mg, 0.237 mmol, prepared as described in Davisson et al.) as its tris-triethylammonium salt and tri-n-butylamine (0.113 ml, 0.474 mmol) were shaken in dry methanol (5 ml) until dissolution was achieved, then the solution was evaporated under reduced pressure. The residue was coevaporated with pyridine (3 x 10 ml) and further dried in vacuo over P 2 0 5 overnight. The resulting oil was dissolved in dry pyridine (3.6 ml) and this solution was added to the nucleoside activated as above.
  • the reaction mixture was stirred overnight at rt. , then evaporated under reduced pressure.
  • the oily residue was partitioned between dichloromethane (2 x 15 ml) and water (50 ml) , the aqueous layer was evaporated under reduced pressure and the residue was ehromatographed on a DEAE A-25 Sephadex column with gradient elution using aqueous triethylammonium hydrogen carbonate (TEAB) solution pH 7.6 from 0.05 M to 0.5 M in 4 litres.
  • TEAB triethylammonium hydrogen carbonate
  • the product, as its triethylammonium salt was eluted at a concentration of 0.37 M TEAB.
  • the product-containing fractions were pooled and evaporated under reduced pressure.
  • Diadenosine 5 ' , 5 ' ' ' - (P 1 , P 2 -methylene-P 3 -thio) -P 1 .P 3 -trisphosphate fAPSPCH 2 PA) Preparation of Diadenosine 5 ' , 5 ' ' ' - (P 1 , P 2 -methylene-P 3 -thio) -P 1 .P 3 -trisphosphate fAPSPCH 2 PA) .
  • This compound was prepared similarly to diadenosine 5',5'"-(P 1 , P 2 -dichloromethylene-P 3 -thio) -P 1 , P 3 -trisphosphate

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Abstract

La présente invention concerne des composés utilisés dans le traitement ou la prévention de l'infarctus associé à une lésion de perfusion répétée, en particulier l'infarctus cérébral associé à une lésion de perfusion répétée.
PCT/GB1998/002101 1997-07-17 1998-07-16 Utilisation d'adenosine tri- ou tetra-phosphates et de leurs analogues dans le traitement de l'infarctus cerebral WO1999003480A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU83514/98A AU8351498A (en) 1997-07-17 1998-07-16 Use of adenosine tri- or tetra-phosphates and their analogues for the reatment of cerebral infarction

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9715198A GB9715198D0 (en) 1997-07-17 1997-07-17 Treatment and prophylaxis of infarction
GB9715198.9 1997-07-18
GB9719596.0 1997-09-15
GBGB9719596.0A GB9719596D0 (en) 1997-09-15 1997-09-15 Treatment and prophylaxis of infarction

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WO1999003480A1 true WO1999003480A1 (fr) 1999-01-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082397A1 (fr) * 2005-02-03 2006-08-10 Imuthes Limited Nouvelles utilisations de derives de polyphosphate de dinucleotides
US7612094B2 (en) 2002-04-04 2009-11-03 Biogen Idec Ma Inc. Tri-substituted heteroaryls and methods of making and using the same
EP2231688A1 (fr) * 2007-11-23 2010-09-29 Bar-Ilan University Dérivés de nucléosides di- ou tri-phosphates non hydrolysables et leurs utilisations
WO2013132489A1 (fr) * 2012-03-05 2013-09-12 Bar-Ilan University Analogues de nucléoside 5'-phosphorothioate et leurs utilisations

Citations (5)

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Publication number Priority date Publication date Assignee Title
JPS57128700A (en) * 1981-01-31 1982-08-10 Yamasa Shoyu Co Ltd P1-guanosine-5', p4-adenosine-5'-tetraphosphate
EP0437929A2 (fr) * 1989-11-24 1991-07-24 Fujirebio Inc. Utilisation du diadénosin-5',5'''-p1,p4-tétraphosphate pour l'obtention d'un médicament pour le traitement des maladies cardiaques
US5049550A (en) * 1987-11-05 1991-09-17 Worcester Foundation For Experimental Biology Diadenosine 5', 5'"-p1, p4,-tetraphosphate analogs as antithrombotic agents
WO1996040059A1 (fr) * 1995-06-07 1996-12-19 The University Of North Carolina At Chapel Hill Dinucleotides utiles dans le traitement de maladies pulmonaires
WO1997040840A1 (fr) * 1996-05-02 1997-11-06 Prp Inc P1,p4-dithio-p2,p3-monochloromethylene-5',5'''-diadenosine-p1,p4-tetraphosphate utilise comme agent anti-thrombose

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
JPS57128700A (en) * 1981-01-31 1982-08-10 Yamasa Shoyu Co Ltd P1-guanosine-5', p4-adenosine-5'-tetraphosphate
US5049550A (en) * 1987-11-05 1991-09-17 Worcester Foundation For Experimental Biology Diadenosine 5', 5'"-p1, p4,-tetraphosphate analogs as antithrombotic agents
EP0437929A2 (fr) * 1989-11-24 1991-07-24 Fujirebio Inc. Utilisation du diadénosin-5',5'''-p1,p4-tétraphosphate pour l'obtention d'un médicament pour le traitement des maladies cardiaques
WO1996040059A1 (fr) * 1995-06-07 1996-12-19 The University Of North Carolina At Chapel Hill Dinucleotides utiles dans le traitement de maladies pulmonaires
WO1997040840A1 (fr) * 1996-05-02 1997-11-06 Prp Inc P1,p4-dithio-p2,p3-monochloromethylene-5',5'''-diadenosine-p1,p4-tetraphosphate utilise comme agent anti-thrombose

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 8237, Derwent World Patents Index; Class B02, AN 82-78133E, XP002079070 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7612094B2 (en) 2002-04-04 2009-11-03 Biogen Idec Ma Inc. Tri-substituted heteroaryls and methods of making and using the same
WO2006082397A1 (fr) * 2005-02-03 2006-08-10 Imuthes Limited Nouvelles utilisations de derives de polyphosphate de dinucleotides
JP2008528665A (ja) * 2005-02-03 2008-07-31 イムセス リミテッド ジヌクレオチドポリリン酸誘導体の使用法
EP2231688A1 (fr) * 2007-11-23 2010-09-29 Bar-Ilan University Dérivés de nucléosides di- ou tri-phosphates non hydrolysables et leurs utilisations
JP2011504489A (ja) * 2007-11-23 2011-02-10 バーイラン ユニバーシティー 非加水分解性ヌクレオシド二又は三リン酸誘導体及びその使用
WO2013132489A1 (fr) * 2012-03-05 2013-09-12 Bar-Ilan University Analogues de nucléoside 5'-phosphorothioate et leurs utilisations

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