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WO1998016539A1 - Nouveaux derives d'adenosine a action therapeutique - Google Patents

Nouveaux derives d'adenosine a action therapeutique

Info

Publication number
WO1998016539A1
WO1998016539A1 PCT/DK1997/000423 DK9700423W WO9816539A1 WO 1998016539 A1 WO1998016539 A1 WO 1998016539A1 DK 9700423 W DK9700423 W DK 9700423W WO 9816539 A1 WO9816539 A1 WO 9816539A1
Authority
WO
WIPO (PCT)
Prior art keywords
adenosine
thio
pyridyl
piperidinyl
deoxy
Prior art date
Application number
PCT/DK1997/000423
Other languages
English (en)
Inventor
Lars Knutsen
Original Assignee
Novo Nordisk A/S
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
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU43773/97A priority Critical patent/AU4377397A/en
Publication of WO1998016539A1 publication Critical patent/WO1998016539A1/fr

Links

Classifications

    • 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

Definitions

  • the present invention relates to therapeutically active ⁇ /-substituted adenosine and 5'- deoxyadenosine derivatives, further substituted at the ribose 5'- and purine 2- and 6- positions and pharmaceutically acceptable addition salts thereof, and their pharmaceutical compositions as well as methods for using the compounds in the treatment of myocardial and cerebral ischaemia and epilepsy.
  • Adenosine is a naturally occurring purine nucleoside, from which is derived a range of agonists at adenosine receptors having considerable potential in the treatment of human disease (Life Sciences, 1991 , 49, 1435-1453; Journal of Medicinal Chemistry, 1992, 35, 407-422; Annual Reports in Medicinal Chemistry, 1993, 28, 295-304).
  • Adenosine has been shown to have a number of significant effects on the mammalian central nervous system (CNS) (Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; Adenosine in the Nervous System, T.W. Stone, Ed., Academic Press Ltd., London 1991 ) especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108, Trends in Pharmacological Sciences, 1992, 11, 439-445). For example, the concentration of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/anoxia (Brain Research, 1990, 516, 248-256).
  • adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity (Trends in Neurosciences, 1984, 164-168).
  • Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) in the CNS (Nature, 1985, 316, 148-150) especially under ischaemic conditions (Journal of Neurochemistry, 1992, 58, 1683-1690).
  • Adenosine receptors represent a subclass (Pj) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into distinct receptor types which have become known as A 1 t A 2 and A 3 . Extensive research has been carried out in a quest to identify selective ligands at these sites. Selective ligands exist for A 1 t A 2 and A 3 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C, Sammes, P.G.
  • adenosine receptor agonists most selective for the A., receptor over the A 2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example ⁇ /-cyclopentyladenosine (CPA) and N- cyclohexyladenosine (CHA) (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2- chloro- ⁇ /-cyclopentyladenosine (CCPA) (Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337, 687-689).
  • CPA ⁇ /-cyclopentyladenosine
  • CHCA N- cyclohexyladenosine
  • CCPA 2- chloro- ⁇ /-cyclopentyladenosine
  • Adenosine receptors there is evidence for further subdivision of adenosine receptors into the subtypes A 2a , A 2b (of high and low affinity) A 3 and A 4 .
  • the latest status of these subtypes has been reviewed (Drug Development Research, 1993, 28, 207-213; Trends in Pharmacological Sciences 1993, 290-291 ; Pharmacological Reviews, 1994, 46, 143-156).
  • the A 3 receptor (Proceedings of the National Academy of Sciences of the USA, 1992, 89, 7432-7436; Trends in Pharmacological Sciences, 1994, 15, 298-306) appears to be responsible for some of the cardiovascular effects of reference ligands (British Journal of Pharmacology, 1993, 709, 3-5).
  • N 6 - substituted adenosine derivatives compounds substituted on adenosine's 6-amino position are referred to as N- substituted adenosine derivatives.
  • Derivatives of adenosine with the heteroatoms sulphur, oxygen or nitrogen bonded directly to the 6-amino substituent are not common in the chemical literature, but those cases known are summarised below.
  • Derivatives with hydrogen at the purine 2-position include ⁇ /-aminoadenosine, N-[(N- methyl- ⁇ /-phenyl)amino]adenosine, ⁇ /-hydroxyadenosine, ⁇ /-methoxyadenosine and N- benzyloxyadenosine (Journal of Medicinal Chemistry, 1985, 28, 1636-1643); N- ethoxyadenosine (Chemical and Pharmaceutical Bulletin, 1973, 21, 1676-1682; ibid., 1973, 21, 1835-1838); /V-(methylamino) adenosine and ⁇ /-[( ⁇ /-hydroxy- ⁇ /-methyl)- aminojadenosine (Journal of Medicinal Chemistry, 1968, 11, 521-523).
  • EP 181 ,128 and EP 181 ,129 disclose 5'-deoxy adenosine derivatives containing 5'- hydrogen, 5'-halogen and 5'-methylthio, which are claimed to have desirable antiinflam- matory, analgesic as well as CNS and antihypertensive properties respectively.
  • EP 232,813 discloses ⁇ /-substituted adenosines including a larger range of 5'-modified compounds which are also claimed to have desirable CNS and antihypertensive properties.
  • WO 94/02497 reveals certain sulphohydrocarbon derivatives of adenosine, where the possibilty exists for substitution at the 5'-position of the ribose moiety.
  • WO 88/03147 5'- substituted adenosine derivatives with selectivity for the adenosine A 2 receptor are disclosed.
  • adenosine analogues with hydrazone derivatives on the 6- amino function are disclosed as hypotensive agents.
  • adenosine and 2- aminoadenosine derivatives having a -NH-R 2 group joined to the 6-amino function are disclosed as coronary dilators and platelet aggregation inhibitors.
  • a series of 2-, 6- and 8- substituted adenosine derivatives are described having activity as anti- allergy agents.
  • adenosine and 2-haloadenosine analogues having an alkyl, cycloalkyl or an aralkyl group attached to the 6-amino function are described with activity as antidementia agents.
  • EP 402,752 derivatives of adenosine unsubstituted in the 2-position are described which have a substituted heteroaromatic 1-pyrrolyl moiety attached to the 6-amino group.
  • WO 91/04032 methods of preventing neural tissue damage in neurodegenerative diseases by increasing extracellular concentrations of adenosine are described. Examples are given of prodrug esters of AICA riboside which are claimed to be centrally acting neuroprotective agents.
  • analogues of AICA riboside are described which increase extracellular adenosine levels with beneficial effects claimed in peripheral and CNS ischaemia.
  • WO 90/055266 2-(alkylalkynyl)adenosine derivatives are described for treatment of ischaemic disease of the heart and brain.
  • EP 423 777 a method for treating gastrointestinal motility disorders using N(6) (substituted aminoalkyl) adenosine deriva- fives is disclosed.
  • EP 490 818 describes a new use of 2'-0-methyl adenosine derivatives for a range of ailments including neurodegenerative disorders.
  • the present invention relates to new adenosine analogues with ribose moieties optionally modified at C-5 which show potent binding in vitro to the adenosine A ⁇ receptor, and which also display selectivity for A receptor binding in vitro over that to the A 2 receptor subtype.
  • the compounds contained in this invention have a relatively high lipophilicity, especially when compared to adenosine analogues which are not substituted on the 6-amino group or the purine 2-position. This latter property makes these compounds suitable for passage across the blood brain barrier.
  • the compounds are also substrates for nucleoside-specific active transport systems into the CNS across the blood barrier. These useful properties support the notion that the compounds are candidate drugs for treatment of the CNS ailments mentioned within this invention in humans as well as cardiovascular disorders such as myocardial ischaemia.
  • WO 95/07921 Novartis A/S, we have revealed a series of compounds which are modified at the ribose C-5, but contain for example a pyrrolidine or piperidine group which may be optionally substituted with one or two C 1-6 -alkyl groups, C 2 .
  • novel compounds having a heteroaryloxy or heteroarylthio substitution on the pyrrolidine or piperidine nucleus described within this present application have improved aqueous solubility, which renders them suitable for formulation for human use. Furthermore, the compounds described herein, such as the examples containing a pyridylthio- functionality show superior potency to other adenosine agonists tested in the gerbil model of severe temporary forebrain ischaemia.
  • the compounds of the invention are purine derivatives of formula I, or a pharmaceutically acceptable salt thereof:
  • •O is the residue of a 4- to 7-membered heterocycle containing at least one nitrogen heteroatom, said heterocycle being substituted with the group -Y-Z;
  • X is halogen, amino, C 1-6 -alkoxy, C 1-6 -alkylthio or C 1-e -alkylamino; A is hydroxymethyl or haiomethyl;
  • Y is oxygen, sulphur, sulphinyl or sulphonyl
  • Z is a five- or six-membered heterocycle, optionally substituted by C 1-6 -alkyl, C ⁇ -alkoxy, C 1-6 -alkylthio or C 1-6 -alkylamino.
  • the 6-amino substituent can contain one or more asymmetric carbon atoms in addition to those asymmetric centres already present in the molecule. In examples where this is the case, this invention includes all resulting diastereoisomers and mixtures thereof.
  • the 4- to 7-membered heterocycle is preferably a five- or six-membered heterocycle, more preferably piperidinyl or pyrrolidinyl, still more preferably piperidinyl;
  • X is preferably halogen
  • Y is preferably oxygen or sulphur, more preferably sulphur
  • Z is preferably thiazole, 1 ,2,4-triazole, imidazole or pyridyl, more preferably pyridyl;
  • A is preferably haiomethyl, more preferably chloromethyl.
  • the present invention furthermore relates to a method of treating myocardial or cerebral ischaemia (disorders where the blood flow to the brain is interrupted) and epilepsy, comprising administering to a subject in need thereof a compound of formula (I) and the use of a compound of formula (I) for the preparation of a medicament for treating epilepsy or ischaemia.
  • salts of compounds of formula (I) can be prepared which is physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutarates, glutaconates, lactates, maleates, methanesul- phonates, phosphates, salicylates, succinates, sulphates, sulphamates, tartrates and paratoluenesulphonat.es. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
  • Compounds of formula (I), which act as adenosine receptor agonists, are furthermore useful in the treatment of central nervous system conditions such as anxiety, neuronal ischaemia/anoxia, convulsive disorders and neurodegeneration (including Parkinson's disease) in humans. This includes treating disorders where the blood flow to the brain is interrupted, for example during traumatic head injury, cardiac arrest and stroke. Further, the compounds of formula (I) are useful as analgesic agents, in lowering plasma free fatty acid (FFA) levels or as cardiovascular agents.
  • FFA plasma free fatty acid
  • the compounds according to the invention possess desirable central nervous system properties. For example, they act as anticonvulsant agents, are effective in animal models of pain, and show cerebroprotective effects in laboratory test animals subjected to simulated cerebral ischaemia. In addition, the compounds may have efficacy as neuroprotective agents in cases of cerebral oedema and traumatic head injury.
  • the affinity of the novel compounds described in this invention for the adenosine Aj receptor was determined essentially as described in the literature using [ 3 H]-R-PIA as a radioligand (Naunyn-Schmiedeberg's Archives of pharmacology, 1980, 313, 179-187). Affinity for the A ⁇ receptor was measured using the radioligand [ 3 H]-CGS 21680 (European Journal of Pharmacology, 1989, 168, 243-246), and the values for representa- tive compounds is given in the table below.
  • the compounds of the invention together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets of filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the adenosine receptor agonist commensurate with the intended daily dosage range to be employed.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparation, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • a syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.
  • the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains:
  • the compounds of the invention may be administered to a subject, e.g., a living animal body, including a human, in need of adenosine receptor agonist, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount of adenosine receptor agonist, and in any event an amount which is effective for the treatment of the disease.
  • a pharmaceutically acceptable acid addition salt thereof such as the hydrobromide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to
  • Suitable dosage ranges are 1-200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • TLC thin layer chromatography
  • THF tetrahydrofuran
  • TFA trifluoracetic acid
  • mp melting point. Where melting points are given, these are uncorrected.
  • Compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. on a Merck Hitachi model L6200A Intelligent chroma- tograph interfaced to a Merck Hitachi L4000A UV detector to a LiChrospher 100 reversed phase C 18 column (5mm, 250 x 4 mm, 5mm, 10 ⁇ A; eluent flow rate 1 mlJmin). Retention times are given in minutes.
  • This compound was prepared from 4-(4-pyridylthio)piperidine (1.78 g, 6.7 mmol) by the method described in Example 4, via the intermediate 2 ' 3 ' 5 ' -tri-0-acetyl-2-chloro- ⁇ /-[4-(4- pyridylthio)-1-piperidinyl]adenosine (0.61 g), which was deacylated to provide the title compound (0.43 g) as a foam; ⁇ NMR (400MHz, DMSO-d 6 ) d 3.52 - 3.58 (1 H, m, H-5' a ), 3.62 -3.69 (1 H, m, H-5' b ), 3.94 (1 H, q, H-4'), 4.13 (1 H, q, H-3'), 4.51 (1H, q, H-2'), 5.06 (1 H, t, 5'-0H), 5.21 (1 H, d, 3'-OH), 5.48 (1H, d, 2'
  • This compound was prepared from 1-amino-4-(2-pyridylthio)pipehdine (prepared by the method described in Example 4) (0.78 g, 3.71 mmol) was reacted with 2-fluoro-9-(2 ' 3 ' 5 ' - tri-0-acetyl-b-D-ribofuranosyl)-6-chloro-9H-purine (see WO 93/08206; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) ( 3.20 g, 7.42 mmol) in the presence of triethylamine, followed by deacylation as described above, to provide the title compound 2-fluoro- ⁇ /-[4-(2-pyridyl)thio-1-piperidinyl]adenosine (0.37g, 21 %) as a foam; 1 H NMR (300MHz, DMSO-d 6 ) d 3.56 (1 H, m, H-5' a ), 3.64 (1 H, m, H

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  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
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Abstract

Cette invention se rapporte à de nouveaux dérivés d'adénosine à action thérapeutique, représentés par la formule générale (I), où (a) représente le reste d'un hétérocycle à 4-7 éléments, contenant au moins un hétéroatome d'azote, cet hétérocycle étant substitué par le groupe -Y-Z; X représente halogène, amino, alcoxy C1-6, alkylthio C1-6 ou alkylamino C1-6; A représente hydroxyméthyle ou halométhyle; X représente oxygène, soufre, sulfinyle ou sulfonyle; et Z représente un hétérocycle à cinq ou six éléments, éventuellement substitué par alkyle C1-6, alcoxy C1-6, alkylthio C1-6 ou alkylamino C1-6. Cette invention se rapporte en outre à des sels d'addition de ces dérivés, acceptables sur le plan pharmaceutique, et à leurs compositions pharmaceutiques, ainsi qu'à des procédés d'utilisation de ces composés dans le traitement de l'ischémie myocardique et cérébrale et de l'épilepsie.
PCT/DK1997/000423 1996-10-14 1997-10-02 Nouveaux derives d'adenosine a action therapeutique WO1998016539A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43773/97A AU4377397A (en) 1996-10-14 1997-10-02 Novel therapeutically active adenosine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1136/96 1996-10-14
DK113696 1996-10-14

Publications (1)

Publication Number Publication Date
WO1998016539A1 true WO1998016539A1 (fr) 1998-04-23

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067262A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives d'adenosine
WO2002069982A1 (fr) * 2001-03-06 2002-09-12 Glaxo Group Limited Medicaments
WO2002074781A1 (fr) * 2001-03-20 2002-09-26 Glaxo Group Limited Procede de preparation de nucleosides de ribofuranose aminopurine substitues en n6
US6495528B1 (en) 1998-06-23 2002-12-17 Smithkline Beecham Corporation 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives
US6762170B1 (en) 1998-01-31 2004-07-13 Smithklinebeecham Corporation 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US7022681B2 (en) * 2002-08-15 2006-04-04 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
US7414036B2 (en) 2002-01-25 2008-08-19 Muscagen Limited Compounds useful as A3 adenosine receptor agonists
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0490818A1 (fr) * 1990-12-07 1992-06-17 Sandoz Ltd. Hydrate de 6-cyclohexyl-2'-0-methyl-adenosine et son utilisations
WO1993008206A1 (fr) * 1991-10-24 1993-04-29 Novo Nordisk A/S Nouveaux derives de purine 2,6-disubstitues
WO1995007921A1 (fr) * 1993-09-17 1995-03-23 Novo Nordisk A/S Composes chimiques, leur preparation et leur utilisation
WO1995028160A1 (fr) * 1994-04-19 1995-10-26 Rhone-Poulenc Rorer Pharmaceuticals Inc. Composes presentant des proprietes anti-hypertensives, cardioprotectrices, anti-ischemiques et antilipolytiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0490818A1 (fr) * 1990-12-07 1992-06-17 Sandoz Ltd. Hydrate de 6-cyclohexyl-2'-0-methyl-adenosine et son utilisations
WO1993008206A1 (fr) * 1991-10-24 1993-04-29 Novo Nordisk A/S Nouveaux derives de purine 2,6-disubstitues
WO1995007921A1 (fr) * 1993-09-17 1995-03-23 Novo Nordisk A/S Composes chimiques, leur preparation et leur utilisation
WO1995028160A1 (fr) * 1994-04-19 1995-10-26 Rhone-Poulenc Rorer Pharmaceuticals Inc. Composes presentant des proprietes anti-hypertensives, cardioprotectrices, anti-ischemiques et antilipolytiques

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6762170B1 (en) 1998-01-31 2004-07-13 Smithklinebeecham Corporation 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6492348B1 (en) 1998-06-23 2002-12-10 Smithkline Beecham Corporation Adenosine derivatives
WO1999067262A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives d'adenosine
US6495528B1 (en) 1998-06-23 2002-12-17 Smithkline Beecham Corporation 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives
US6677316B2 (en) 1998-06-23 2004-01-13 Smithkline Beecham Corporation Adenosine derivatives and methods of administration
EP1447407A1 (fr) * 1998-06-23 2004-08-18 Glaxo Group Limited Dérivés d'adénosine
BG65064B1 (bg) * 1998-06-23 2007-01-31 Glaxo Group Limited Аденозинови производни
WO2002069982A1 (fr) * 2001-03-06 2002-09-12 Glaxo Group Limited Medicaments
WO2002074781A1 (fr) * 2001-03-20 2002-09-26 Glaxo Group Limited Procede de preparation de nucleosides de ribofuranose aminopurine substitues en n6
US7297787B2 (en) 2001-03-20 2007-11-20 Glaxo Group Limited Process for preparing N6 substituted aminopurine ribofuranose nucleosides
US7414036B2 (en) 2002-01-25 2008-08-19 Muscagen Limited Compounds useful as A3 adenosine receptor agonists
US7022681B2 (en) * 2002-08-15 2006-04-04 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor

Also Published As

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AU4377397A (en) 1998-05-11
ZA978948B (en) 1998-04-14

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