[go: up one dir, main page]

WO1994017803A9 - Inhibiteurs de l'adenosine kinase - Google Patents

Inhibiteurs de l'adenosine kinase

Info

Publication number
WO1994017803A9
WO1994017803A9 PCT/US1994/001340 US9401340W WO9417803A9 WO 1994017803 A9 WO1994017803 A9 WO 1994017803A9 US 9401340 W US9401340 W US 9401340W WO 9417803 A9 WO9417803 A9 WO 9417803A9
Authority
WO
WIPO (PCT)
Prior art keywords
amino
hydrogen
halogen
deoxy
alkyl
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.)
Ceased
Application number
PCT/US1994/001340
Other languages
English (en)
Other versions
WO1994017803A1 (fr
Filing date
Publication date
Application filed filed Critical
Priority to EP94909558A priority Critical patent/EP0682519A4/fr
Priority to AU62365/94A priority patent/AU6236594A/en
Publication of WO1994017803A1 publication Critical patent/WO1994017803A1/fr
Publication of WO1994017803A9 publication Critical patent/WO1994017803A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Definitions

  • This invention relates to the use of adenosine kinase inhibitors and specifically to purine, pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine nucleoside analogs having activity as adenosine kinase inhibitors.
  • the inventio also relates to the use of these and other adenosine kinase inhibitors in the treatment of inflammation, sepsis, septic shock, burns and diseases which can b regulated by increasing the local concentration of adenosine.
  • Circulation. 1987, 76:1135-1145 and neuroprotective properties (Dragunow an Fault, Trends in Pharmacol. Sc 1988, 9:193; Marangos, Medical Hypothesis, 1990, 32:45). It is reportedly released from cells in response to alterations in the supply of or demand for oxygen (Schrader, Circulation. 1990, 81:389-391), is sai to be a potent vasodilator, and is believed to be involved in the metabolic regulation of blood flow (Berne, Circ. Res.. 1980, 47:808-813). However, adenosine has a short half life ( ⁇ 1 sec) in human blood (Moser, et al., Am. J.
  • PhvsioL 1989, 256:C799-C806) and therefore high doses of adenosine would need to be administered continuously to achieve effective levels.
  • Adenosine has been reported to exhibit negative inotropic, chronotropic and dromotropic effects (Belardinelli et al., Prog, in Cardiovasc. Diseases. 1989, 32:73-97) and to cause coronary steal by preferentially dilating vessels in nonischemic regions. Consequently, high doses of adenosine are toxic and this toxicity severely limits i therapeutic potential. However, it is believed that by increasing adenosine concentration locally, i.e.
  • Adenosi has been reported to be an endogenous modulator of inflammation by virtue of it effects on stimulated granulocyte function (Cronstein et al., J. Clin. Invest.. 1986, 78:760-770) and on macrophage, lymphocyte and platelet function. Adenosine receptor agonists have been reported to be beneficial in an experimental model inflammation (Schrier. et al.. J. Immunol.. 1990, 145:1874-1879).
  • Adenosine an related analog have been reported to inhibit in vitro production of the cytokine, tumor necrosis factor alpha (Parmely et al., FASEB Journal. 1991 , 5: A 1602).
  • Adenosine kinase is a cytosolic enzyme which catalyzes the phosphorylation of adenosine to AMP. Inhibition of adenosine kinase can potentially reduce the ability of the cell to utilize adenosine, leading to increased adenosine outside of the eel! where it is pharmacologically active.
  • Adenosine can also be deaminated to inosine by adenosine deaminase (ADA) and condensed with L-homocysteine to S- adenosylhomocysteine (SAH) by SAH hydrolase.
  • ADA adenosine deaminase
  • SAH S- adenosylhomocysteine
  • nucleosides including purine, pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine analogs have been evaluated for inhibition of adenosi kinase but were reported to have Kj's of greater than 800 nM (Caldwell and Henderson, Cancer Chemother. Rep.. 1971 , 2:237-246; Miller et al., J. Biol. Che 1979, 254:2346-2352). A few compounds have been reported as potent inhibito of adenosine kinase with Ki's of less than 100 nM.
  • adenosine release has been measured in neuroblastoma cells in culture and compared with that of a variant deficient in adenosine kinase (AK-).
  • AK- adenosine kinase
  • adenosine uptake was reportedly inhibited by the adenosine kinase inhibitors, 5 iodotubercidin and 5'-deoxy-5-iodotubercidin (Davis et al., Biochem. Pharmacol.
  • 5-iodotubericidin were evaluated in an experimental model in which d hearts were subjected to ischemia and reperfusion; 5-iodotubericidin was report to have inconsistent effects (Wu, et al., Cvtobios. 1987, 50:7-12).
  • mice 25 activity in mice, interpreted to be skeletal muscle relaxation; to cause hypothermi in mice; and to decrease blood pressure and heart rate in anesthetized rats (Da et al., Biochem. Pharmacol.. 1984, 33:347-355; Daves et al., Biochem. Pharmac 1986, 35:3021-3029; U.S. Patent No. 4,455,420).
  • the skeletal muscle effects of these compounds have been poorly documented, while the other effects were considered significant toxicities. It is believed that studies using these compoun were curtailed due to these toxicities and also because of their limited availability
  • the present invention is directed to novel uses of compounds which are potent and selective adenosine kinase inhibitors.
  • Another aspect of the present invention is directed to the clinical use of adenosine kinase inhibitors as a method of increasing adenosine concentrations biological systems, in vivo inhibition of adenosine kinase prevents phosphorylation of adenosine resulting in higher local concentrations of endogenous adenosine.
  • adenosine kinase inhibitors As a result of the very short half-life of adenosine and very low quantities of adenosine in tissues, this effect is most pronounced in regions producing the most adenosine such as ischemic regions. Hence, the beneficial effects of adenosine are enhanced in a site and event specific manner and toxic systemic effects are reduced.
  • the present invention is directed to novel nucleoside analogs which comprise a S'-modified ribose linked to a substituted purine, pyrrolo[2,3-d]pyrimidine, or pyrazolo[3,4-d]pyrimidine base.
  • Certain preferred compounds within these groups possess potencies many time greater than previously described inhibitors of adenosine kinase.
  • the compoun of the present invention possess advantages for pharmaceutical use such as enhanced pharmacological selectivity, efficacy, bioavailability, ease of manufact and compound stability.
  • novel compounds of the present invention and other adenosine kinas inhibitors may be used clinically to treat medical conditions where an increased localized adenosine concentration is beneficial.
  • the present inventi is directed to the prophylactic and affirmative treatment of ischemic conditions su as myocardial infarction, angina, percutaneous transluminal coronary angiograp (PTCA), stroke, other thrombotic and embolic conditions, neurological conditions such as seizures and psychosis, and other conditions benefited by enhanced adenosine levels such as inflammation, arthritis, autoimmune diseases, cardiac arrhythmias, ulcers and irritable bowel syndrome.
  • ischemic conditions su as myocardial infarction, angina, percutaneous transluminal coronary angiograp (PTCA), stroke, other thrombotic and embolic conditions, neurological conditions such as seizures and psychosis, and other conditions benefited by enhanced adenosine levels such as inflammation, arthritis, autoimmune diseases, cardiac arrhythmias, ulcers and irritable
  • the present invention is also directed to the prophylactic and affirmative treatment of sepsis, septicemia (including but not limited to endotoxemia), and various forms of septic shock (including but not limited to endotoxic shock.)
  • septicemia including but not limited to endotoxemia
  • septic shock including but not limited to endotoxic shock.
  • adenosine kinase inhibitors will be useful in the prophylactic or affirmative treatment of a localized or systemic inflammatory response to infection by one or more of several types of organisms, including bacteria (gram negative or gram positive), viruses (including retroviruses), mycobacteria, yeast, protozoa or parasites.
  • the present invention is directed to the treatment of disorders which vascular leakage is involved.
  • the present invention is directe to the treatment of burn injury.
  • hydrocarbyl refers to an organic radical comprised of carbon chains to which hydrogen and other elements are attached.
  • the term includes alkyl, alkenyl, alkynyl and aryl groups, groups which have a mixture of saturated and unsaturated bonds, carbocyclic rings and includes combinations of such groups. It may refer to straight-chain, branched-chain cyclic structures or combinations thereof.
  • aryl refers to aromatic groups which have at least one ring havi a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl biaryl groups, all of which may be optionally substituted.
  • Carbocyclic aryl groups are groups wherein the ring atoms on the aromati ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic groups and optionally substituted naphthyl groups.
  • the term "monocyclic carbocyclic aryl” refers to optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituent such being advantageously lower alkyl, hydroxy, lower alkoxy, lower alkanoylox halogen, cyano, trihalomethyl, lower acylamino or lower alkoxycarbonyl.
  • Optionally substituted naphthyl refers to 1- or 2-naphthyl or 1- or 2-napht preferably substituted by lower alkyl, lower alkoxy or halogen.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as rin atoms in the aromatic ring and the remainder of the ring atoms carbon atoms. Suitable heteroatoms include oxygen, sulfur, and. nitrogen, and include furanyl, i o thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl, an the like, all optionally substituted.
  • Optionally substituted furanyl represents 2- or 3-furanyl or 2- or 3-furanyl preferably substituted by lower alkyl or halogen.
  • Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl or 2-, 3- or 4- 15 pyridyl preferably substituted by lower alkyl or halogen.
  • Optionally substituted thienyl represents 2- or 3-thienyl, or 2- or 3-thienyl preferably substituted by lower alkyl or halogen.
  • biasing represents phenyl substituted by carbocyclic aryl or heterocyclic aryl as defined herein, ortho, meta or para to the point of attachment 20 the phenyl ring, advantageously para; biaryl is also represented as the -C6H4-A substituent where Ar is aryl.
  • aralkyl refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optional substituted. 25
  • lower referred to herein in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up t and including 4 and advantageously one or two carbon atoms. Such groups ma be straight chain or branched.
  • alkyl amino refers to the groups -NRR' wherein respectively, (a) R is alkyl and R' hydrogen or alkyl; (b) R is aryl and R' is hydrogen or aryl, and (c) R is aralkyl and is hydrogen or aralkyl.
  • acyl refers to hydrocarbyl-C(O)- or HC(O)-.
  • acylamino refers to RC(0)NR- and (RC(0))2N- respectively, wherein each R is independently hydrogen or hydrocarbyl.
  • ⁇ -alkoxyalkylidene refers to hydrocarbyl-O-CR (an orthoester) wherein R is hydrogen or hydrocarbyl.
  • hydrocarbyloxycarbonyloxy refers to the group ROC(0)0- wherein R is hydrocarbyl.
  • lower carboalkoxymethyl or “lower hydrocarbyloxycarbonymethyl” refers to hydrocarbyl-OC(0)CH2- with the hydrocarbyl group containing ten or less carbon atoms.
  • carbonyl refers to -C(O)-.
  • carboxamide or “carboxamido” refers to -CONR2 wherein each is independently hydrogen or hydrocarbyl.
  • lower hydrocarbyl refers to any hydrocarbyl group of ten or les carbon atoms.
  • alkyl refers to saturated aliphatic groups including straight-chai branched chain and cyclic groups.
  • alkenyl refers to unsaturated hydrocarbyl groups which contain least one carbon-carbon double bond and includes straight-chain, branched-ch and cyclic groups.
  • alkynyl refers to unsaturated hydrocarbyl groups which contain least one carbon-carbon triple bond and includes straight-chain, branched-chai and cyclic groups.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydrocarbyloxycarbonylamino refers to a urethane, hydrocarb O-CONR- wherein R is H or hydrocarbyl and wherein each hydrocarbyl is independently selected.
  • di(hydrocarbyloxycarbonyl)amino refers to (hydrocarbyl-O- CO)2N- wherein each hydrocarbyl is independently selected.
  • hydrocarbyiamino refers to -NRR' wherein R is hydrocarbyl an is independently selected hydrocarbyl or hydrogen.
  • mercapto refers to SH or a tautomeric form.
  • metal refers to H-C t -
  • methylene refers to -CH2-.
  • alkylene refers to a divalent straight chain or branched chain saturated aliphatic radical.
  • oxy refers to -O- (oxygen).
  • thio refers to -S- (sulfur).
  • prodrug refers to any compound that has less intrinsic activity than the "drug” but when administered to a biological system generates the "drug” substance either as a result of spontaneous chemical react or by enzyme catalyzed or metabolic reaction.
  • prodrugs such as acyl esters, carbonates, and urethanes, included herein as examples.
  • the groups illustrated are exemplary, not exhaustive and one skilled the art could prepare other known varieties of prodrugs.
  • prodrugs of the compounds of Formula I fall within the scope of the present invention.
  • pharmaceutically acceptable salt includes salts of compounds
  • Formula I derived from the combination of a compound of this invention and an organic or inorganic acid.
  • the compounds of Formula I are useful in both free b and salt form.
  • salt form amounts to use of base form; both forms are within the scope of the present invention.
  • Figure 1 depicts the effects of the adenosine kinase inhibitor GP-1-238 o mean arterial pressure, heart rate and body temperature following intravenous administration to anesthetized or conscious rats.
  • Figure 2 depicts the dose-dependent inhibition of neutrophil adhesion to endotheiial cells by the adenosine kinase inhibitors GP-1-272 and GP-1-456 an the reversal of this inhibition by co-treatment with adenosine deaminase ("ADA"
  • Figures 3 to 7 depict reaction schemes for preparing certain of these adenosine kinase inhibitors.
  • Figure 8 depicts the structures of certain preferred intermediates useful in the synthesis of adenosine kinase inhibitors.
  • Figure 9 depicts the effect of the adenosine kinase inhibitor, GP-1-515, in protecting against endotoxic shock and also depicts the effect of the adenosine receptor antagonist, 8-p-sulphophenyltheophylline, in blocking the GP-1-515- induced protection.
  • Figure 10 depicts the effect of the adenosine kinase inhibitor, GP-1-515, survival of rats after cecal ligation and puncture.
  • Figure 11 depicts the effect of the adenosine kinase inhibitor, GP-1-515, blood tumor necrosis factor alpha levels in endotoxic shock in mice.
  • Figures 12a to e show GP-1-515 improves gas exchange, prevents acido and decreases tachycardia in endotoxic shock in miniature pigs. Anesthetized animals were ventilated with constant Fi ⁇ 2 and tidal volume throughout the stud
  • Figure 13 depicts the effect of the adenosine kinase inhibitor GP-1-792 in the suppression of carrageenan and histamine induced plasma leakage followi intradermal injections in rats.
  • the present invention relates to the novel use of adenosine kinase inhibitors which comprise compounds of the general formula I.
  • A is oxygen, methylene or sulfur
  • B' is -(CH2)n-B wherein n is 1 , 2, 3 or 4 and B is hydrogen, alk alkoxy, amino, alkylamino, acylamino, hydrocarbyloxycarbonylamino, mercapto alkylthio, azido, cyano, halogen, or B' is alkenyl or alkynyl;
  • Ci and C-2 are each independently hydrogen, acyl, hydrocarbyloxycarbonyl or taken together form a 5-membered ring wherein Ci single bond to C2 and C2 is carbonyl or ⁇ -alkoxyalkylidene;
  • D is hydrogen, halogen, alkyl, aryl, aralkyl, alkenyl, alkynyl, haloalkyl, cyano, cyanoalkyl, acyl, carboxamido, a carboxylic acid or carboxylic acid ester group, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio, amin alkylamino arylamino, aralkylamino, acylamino, or nitro;
  • E is hydrogen, halogen, alkyl, or alkylthio
  • novel adenosi kinase inhibitors which have a 5'-group which comprises a hydroxyl or hydroxyl derivative.
  • those compounds which have a 5'-hydroxyl would not act as substrates for phosphorylation enzymes and, thus, would be unlikely to undergo 5'- phosphorylation or would be phosphorylated at an extremely slow rate.
  • adenosine kinase inhibitors comprise compounds of the formula:
  • A is oxygen, methylene or sulfur
  • B' is -(CH2)nB wherein n is 1 , 2, 3 or 4 and B is hydroxy, acyloxy hydrocarbyloxycarbonyloxy, or -OCONR2 wherein each R is independently hydrocarbyl;
  • D is halogen, aryl or aralkyl
  • F is alkyl, aryl, aralkyl, halogen, amino, alkylamino, arylamino, aralkylamino, cyano, cyanoalkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, aralkylthio, optionally substituted indolinyl or indolyl, pyrroiidinyl or piperazinyl;
  • G is hydrogen, halogen, lower alkyl, lower alkoxy, or lower alkylthio; and pharmaceutically acceptable salts thereof; with the proviso that wh A is oxygen and D is halogen, then F is not amino.
  • adenosine kinase inhibitors comprise compounds of the formula:
  • A is oxygen, methylene or sulfur
  • B' is -(CH2)r .
  • B wherein n is 1 , 2, 3 or 4 and B is hydroxy, acylox hydrocarbyloxycarbonyloxy, or -OCONR2 wherein each R is independently hydrocarbyl;
  • Ci and C2 are each independently hydrogen, acyl, hydrocarbyloxycarbonyl or taken together form a 5-membered ring wherein Ci i single bond to C2 and C2 is carbonyl or ⁇ -alkoxyalkylidene;
  • D is aryl or aralkyl
  • E is hydrogen, halogen, alkyl, or alkylthio
  • F is alkyl, aryl, aralkyl, halogen, amino, alkylamino, arylamino, aralkylamino, cyano, cyanoalkyl, alkoxy, aryloxy, aralkyioxy, alkylthio, arylthio, aralkylthio, optionally substituted indolinyl or indolyl, pyrroiidinyl or piperazinyl; (h) G is hydrogen, halogen, lower alkyl, lower alkoxy, or lower alkylthio; and pharmaceutically acceptable salts thereof; with the proviso that: w A is oxygen, D is oxadiazolyl, t ⁇ azolyl or triazinyl, E and G are both hydrogen, th
  • adenosine kinase inhibitor which comprise modified purine nucleosides of the formula:
  • A is oxygen, methylene or sulfur;
  • B 1 is -CH2B wherein and B is amino, alkylamino, or acylamino;
  • Ci and C2 are each independently hydrogen, acyl, hydrocarbyloxycarbonyl or taken together form a 5-membered ring wherein Ci i single bond to C-2 and C2 is carbonyl or ⁇ -alkoxyalkylidene;
  • E is hydrogen, halogen, alkyl, amino, alkylamino, azido, acylamino, alkoxy or alkylthio;
  • F is halogen, amino, alkylamino, arylamino, aralkylamino, cyanoalkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, aralkylthio, alkyl, aryl, aralkyl, option substituted indolinyl or indolyl, pyrroiidinyl or piperazinyl; and (g) G is hydrogen, halogen, lower alkyl, lower alkoxy, or lower alkylthio an pharmaceutical acceptable salts thereof; with the proviso that: when A is oxygen, B is amino or hydrocarbylamino, E and G are hydroge then F is not amino.
  • novel adenosine kinase inhibitors comprise dimeric compounds of the formula: wherein
  • a and A' are independently oxygen, methylene or sulfur;
  • B' and B" are independently -(CH2)nB wherein n is independently 1 , or 4 and B is independently hydrogen, hydroxy, alkyl, alkoxy, amino, alkylamino acylamino, hydrocarbyloxycarbonylamino, mercapto, alkylthio, azido, or either both of B' or B" is independently alkenyl or alkynyl;
  • Ci and C-r and C2 and C2' are each independently hydrogen, acyl, hydrocarbyloxycarbonyl, or Ci and C2 or C and C2' taken together form a 5- membered ring wherein Ci or C is a single bond to C2 or C2' and C2 or C-2' i carbonyi or ⁇ -alkoxyalkylidene;
  • D is independently hydrogen, halogen, alkyl, aryl, aralkyl, alkenyl, alkynyl, haloalkyl, cyano, cyanoalkyl, acyl, carboxamido, a carboxylic acid or corresponding carboxylic acid ester group, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio, amino, alkylamino, arylamino, aralkylamino acylamino or ni
  • E is independently hydrogen, halogen, alkyl, or alkylthio;
  • L is an optionally substituted piperaz
  • ALKL is a divalent alkylene radical of 2 to 24 carbon atoms
  • G is hydrogen, halogen, alkyl alkylthio.
  • Especially preferred G groups include hydrogen.
  • Preferred Ci and C2 groups include hydrogen and acetyl.
  • E groups include hydrogen or halogen, especially preferred are compounds where E is hydrogen.
  • D is hydrogen, halogen, alkyl, aryl, aralky alkenyl or alkynyl, cyano, cyanoalkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, aralkylthio, amino, alkylamino, arylamino, aralkylamino, carboxamido, or hydrocarbyloxycarbonyl.
  • D groups include hydrogen, halogen, alkyl, aryl, aralkyl, cyano, alkoxy, aryloxy, aralkoxy, alkenyl or alkynyl, more preferably hydrogen, halogen, aryl, cyano, alkoxy or aryloxy.
  • a particularly preferred group of compounds include those wherein D is hydrogen, halogen or aryl.
  • D is aryl such as heterocyclic aryl or monocyclic carbocyclic aryl, such as optionally substituted phenyl.
  • B' is -(CH2)nB, and n is 1 or 2, more preferably n is 1.
  • B may preferably include hydrogen, halogen, alkyl, amino alkylamino, alkoxy, mercapto, alkylthio, azido or cyano; more preferably B is hydrogen, halogen, lower alkyl, amino, lower alkylamino, azido or cyano.
  • Particularly preferred B groups include hydrogen, amino or azido.
  • B' is vinyl, ethynyl, or propargyl.
  • Preferred F groups include halogen, amino, alkylamino, arylamino, aralkylamino, alkylthio, arylthio, alkyl, aryl or aralkyl, more preferably amino or arylamino.
  • preferred F groups include optionally substituted anilino.
  • the compounds of the present invention contain asymmetric carbon atom and hence can exist as stereoisomers, both enantiomers and diastereomers. Th individual preferred stereoisomers and mixtures thereof are considered to fall within the scope of the present invention.
  • the compounds described by Formula contain a 5-modified 1- ⁇ -D-ribofuranosyl group and that isomer comprises a particularly preferred diastereomeric and enantiomeric form for compounds of th present invention.
  • the synthetic examples cited herein provide the most preferred isomer.
  • compounds of Formula I where B is hydroxy are in many cases potent inhibitors of adenosine kinase.
  • the use of compounds having Formula I wherein B' replaced by -CH2OH, as adenosine kinase inhibitors are included in the scope of this invention.
  • these compounds may be phosphorylated in vjvg. and since the resulting 5'- phosphates may be toxic, mutagenic or teratogenic, ⁇ '-hydroxy compounds whic can serve as substrates for phosphorylation enzymes may not comprise preferre compounds for clinical or therapeutic use.
  • Preferred adenosine kinase inhibitor compounds of the present invention include certain pyrazolo[3,4-d]pyrimidine compounds of Formulas I and II.
  • Preferred pyrazolo[3,4-d]pyrimidine compounds of Formula I include thos where G is hydrogen and A is oxygen.
  • Preferred D groups include hydrogen, al aryl, aralkyl, cyano, alkoxy, aryloxy, aralkoxy, alkenyl or alkynyl, more preferably hydrogen, halogen, aryl, cyano, alkoxy or aryloxy, more particularly hydrogen, halogen or aryl.
  • An especially preferred group of compounds includes those where D is aryl, especially heterocyclic aryl or monocyclic carbocyclic aryl, more preferably optionally substituted phenyl.
  • Preferred B' groups include -(CH2)nB wherein B is hydrogen, halogen, alkyl, amino, alkylamino, alkoxy, mercapto, alkylthio, azido or cyano; more preferably B is hydrogen, halogen, lower alkyl, amino, lower alkylamino, azido or cyano. Particularly preferred B groups include hydrogen, amino or azido. Preferably, n is 1 or 2, more preferably 1. Other preferred B' groups include vinyl and ethynyl.
  • Cer preferred compounds include F groups which comprise optionally substituted anilino.
  • Examples of preferred pyrazolo[3,4-d]pyrimidine compounds include tho noted as GP-1-515, GP-1-547, GP-1-560, GP-1-665, GP-1-666 GP-1-667, GP-1- 695, GP-1 -704, and GP-1 -792.
  • Preferred pyrazolo[3,4-d]pyrimidine compounds of Formula II include tho where G is hydrogen and A is oxygen.
  • Preferred D groups include aryl.
  • Preferr aryl groups include heterocyclic carbocyclic aryl groups, especially optionally substituted phenyl.
  • Preferred F groups include halogen, amino, alkylamino, arylamino, aralkylamino, alkylthio, arylthio, alkyl, aryl, or aralkyl, more preferably amino or arylamino.
  • Certain preferred compounds of Formula II may include F groups which comprise optionally substituted anilino groups.
  • Preferred Pyrrolor2.3-dlpyrimidines Preferred adenosine kinase compounds of the present invention include pyrrolo[2,3-d]pyrimidine compounds of Formulas I and II.
  • Preferred pyrrolo[2,3-d]pyrimidine compounds of Formula I include those wherein G is hydrogen. Preferred are compounds wherein E is hydrogen or halogen; more preferably E is hydrogen. Preferred are compounds where A is oxygen. Preferred compounds include those where D is hydrogen, halogen, al aryl, aralkyl, cyano, alkenyl or alkynyl, more preferably hydrogen, halogen or ar An especially preferred group of compounds includes those where D is aryi, especially heterocyclic aryl or monocyclic carbocyclic aryl, especially optionally substituted phenyl. Preferred B 1 groups include -(CH2)nB wherein n is 1 or 2, preferably 1.
  • B is hydrogen, halogen, alkyl, amino, alkylamino, alko mercapto, alkylthio, azido or cyano, more preferably B is hydrogen, halogen, low alkyl, amino, lower alkylamino, lower alkoxy, lower alkylthio, or azido, more particularly hydrogen, lower alkyl, amino, lower alkylamino, or azido.
  • B groups include hydrogen, amino or azido.
  • Other preferred B' groups include vinyl and ethynyl.
  • Preferred pyrrolo[2,3-d]pyrimidine compounds of Formula I include those wherein F is halogen, amino, alkylamino, arylamino, aralkylamino, alkylthio, aralkylthio, alkyl, aryl or aralkyl, more preferably amino or arylamino. Certain preferred compounds include F groups which comprise optionally substituted anilino. Examples of preferred pyrrolo[2,3-d]pyrimidine compounds include those noted as GP-1-448, GP-1-606, GP-1-608, GP-1-639, G 1-683, GP-1-684, GP-1-691 , GP-1-711 , GP-1-714, and GP-1-718.
  • Preferred pyrrolo[2,3-d]pyrimidines of Formula II include those where G is hydrogen and A is oxygen.
  • E is hydrogen or halogen, more preferabl hydrogen.
  • Preferred D groups include aryl.
  • Preferred aryl groups include heterocyclic aryl groups and monocyclic carbocyclic aryl groups, especially optionally substituted phenyl.
  • Preferred heterocyclic aryl groups include 2-furany 2-thienyl and 3-thienyl.
  • Preferred purine compounds include those where G is hydrogen, halogen, lower alkyl or lower alkylthio, more preferably hydrogen. Preferred are compoun wherein A is oxygen. Preferred E groups include hydrogen, halogen or alkylthio. Preferred are compounds wherein B is amino. Preferred F groups include halogen, amino, alkylamino, arylamino, aralkylamino, alkylthio, arylthio, alkyl, ary or aralkyl, more preferably amino or arylamino. ⁇ __ ⁇ Preferred Dimer Compounds
  • Preferred dimeric compounds include those which comprise dimers of the above-described pyrazolo[3,4-d]pyrimidines, the pyrrolo[2,3-d]-pyrimidines and purines. These dimers may comprise monomeric units which are the same or different.
  • This invention is also directed to processes for preparing compounds of
  • Formula I Disclosed herein are general synthetic routes for preparing variously substituted purine nucleosides or pyrrolo[2,3-d]pyrimidine nucleosides, includin novel and improved synthesis of 5'-deoxy-5-iodotubercidin; and pyrazolo[3,4- d]pyrimidine nucleosides of the present invention.
  • FIG. 3 A process for preparing 5'-azido, 5'-amino and 5'-deoxy analogs of 6- substituted-amino purine ribosides is depicted in Figure 3.
  • the protected azide (2a.) prepared from 2',3'-0-isopropylideneinosine, is activated for nucleophilic attack at position six by chlorination with thionyl chloride/dimethylformamide.
  • Ot standard reagents may also be used to activate position six of compound (2) su as thionyl bromide, phosphorous oxychloride, triphenylphosphine dibromide- thiophenol-potassium permanganate or hexamethyldisilazane-ammonium sulfa
  • the chloride (3) or other activated intermediate (Br, RSO2, R3SiO, etc.) is then reacted with ammonia or an appropriate amine such as aniline, piperazine or indoline in solvents such as water, alcohols, THF and the like.
  • the resulting protected azide (4a) is deblocked using an aqueous acid such as 50% formic a to provide the 6-substituted-amino 5'-azido-5'-deoxyadenosine (___).
  • Reduction the azide (5a) to the amine ( >) is effected by catalytic hydrogenation with a catal such as platinum oxide, palladium on carbon and the like.
  • a catal such as platinum oxide, palladium on carbon and the like.
  • triphenylphosphi is used to selectively reduce the azide moiety to the amine.
  • N- acylamino (7a) and hydrocarbyioxycarbonylamino (7b) compounds the azide ( is reduced to the amine and treated with an acyl anhydride or acyl chloride or al chloroformate and deblocked to give (7a) or (7b) respectively.
  • Analogous processes are used to prepare the 2- and 8- substituted analogs beginning with appropriately substituted intermediates.
  • An alternative synthesis of 5'-amino an 5'-hydrocarbylamino compounds comprises deblocking a 2',3'-isopropylidene- tosylate with aqueous acid and then reacting the deblocked tosylate with ammo or a lower hydrocarbyiamine. Further description of these procedures is set forth the Examples.
  • the 5-substituted-5-deoxy ribose analogs ( Q) are prepared by tosylation of the protected ribose (fi), displacement of the tosylate by appropriate nucleophiles and subsequent deblocking (Synder, J.; Serianni, A.; Carbohydrate Res.. 1987, 163:169).
  • the ribose homologs ( Figure 5) are prepared by oxidation the protected ribose (S) to the aldehyde (11) (Moorman, A.; Borchaedt, R.; Nuclei Acid Chemistrv-Part III. Townsend, L; Tipson, R.; John Wiley & Sons, 1986).
  • the aldehyde is homologated via the appropriate Wittig reagent to give the key intermediate protected vinyl sugar (12).
  • the protected intermediate is deblocked give the vinyl ribose homolog (16a) or reduced to (IS) and then deblocked to giv the saturated deoxy analog (16b).
  • the vinylated intermediate (12) i hydroborated and oxidized affording the protected homologous ribose (14a) whi is deblocked to the ribose homolog or converted to the azide (14b) via tosylation and displacement with azide. Deblocking of (14b) then affords the homologous azido ribose (16d).
  • the protected 5-aldehyde (11) was also methylated to ultimately afford 6-deoxy-D-allofuranose (16e).
  • the various 5- substituted ribos are then converted to the corresponding 2,3-0-isopropylidine ketals ( Figure 6) which are chlorinated stereoselectively to 5-modified 1-chloro- ⁇ -D-ribofuranosid (17) using carbon tetrachloride and hexamethylphosphorous triamide (Wilcox, Qtaski. R.: Tetrahedron Lett.. 1986, 27:1011).
  • the preparation of various substituted 4-chloro-pyrrolo[2,3-d]pyrimidines i described in the Examples.
  • ribosyl protected 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine nucleosides and the corresponding deblocked compounds are versatile intermediates and comp an aspect of the present invention.
  • the 4-chloro substituent of (IS) can be displaced by sulfur (such as thiourea or mercaptide anions) leading to thionated and hydrocarbylthio compounds. More importantly, displacement of t 4-chloro substituent by ammonia or amines leads to 4-amino- and 4- arylaminopyrrolo[2,3-d]pyrimidine nucleosides.
  • Another aspect of the present invention is directed to the use of arylboron acids to prepare 4- and 5-arylated pyrrolo[2,3-d]pyrimidine bases and nucleosid from the corresponding 4- and 5-halogenated compounds.
  • a halogenate nucleoside such as (19) or the corresponding base was heated with an arylboro acid and a palladium-phosphine catalyst such as palladium tetrakis(triphenylphosphine) to prepare the analogous arylated compound by displacement of halogen.
  • Various 4- and 5- arylated pyrrolo[2,3-d]pyrimidines al can be prepared using arylstannyl compounds in place of the arylboronic acids (Flynn, B.; Macolino, B.; Crisp, G. Nucleosides & Nucleotides. 1991 , 10:763).
  • Synthesis of 5-arylpyrrolo[2,3-d]pyrimidines can also be effected by condensatio of arylamino ketones and malononitrile to arylated pyrroles and subsequent ring closure to 5-arylpyrrolo[2,3-d]pyrimidines. (Taylor, E.; Hendess, R., J. Am. Chem. Soc.
  • Still another aspect of this invention is the preparation of 5'-substituted pyrazolo[3,4-d]pyrimidine ribosides of Formula I as depicted in Figure 7.
  • a substituted pyrazolo[3,4-d]pyrimidine is ribosylated with an esterifi 5-hydroxy, 5-azido or 5-deoxyribofuranoside in the presence of a Lewis acid suc as boron trifluoride (Cottam, H., Petrie, C; McKernan, P.; Goebel, R.; Dalley, N.; Davidson, R.; Robins, R.; Revankar, G.; J. Med. Chem.. 1984, 27:1120).
  • the 5- substituted sugar is prepared by esterification of the deblocked sugar (10a) to (1 or (16a) to (16e) (See Figure 6). Suitable esters include the acetate, benzoate, toluate, anisoate and the like.
  • the substituted pyrazolo[3,4-d]pyrimidine base (2 may be prepared by a variety of procedures as illustrated in the Examples. Two general routes to the compounds of the present invention are described below.
  • the first general route comprises coupling an esterified ribose (21 ), prepared from (10) or (16), with a 3-substituted pyrazolo[3,4-d]pyrimidin-4-one.
  • the pyrimidone riboside (24a) may be activated by chlorination with thionyl chloride/dimethylformamide or other reagents previously described and then reacted with ammonia or an amine to provide a variety of substituted 5' modified N 4 -substituted-amino-pyrazolo[3,4-d]pyrimidine nucleosides (24b).
  • 3-iodopyrazolo[3,4-d]pyrimidone nucleosides are prepared by nonaqueous diazotization-iodination of the 3-ami compounds using a nitrite ester such as isoamyl nitrite and methylene iodide.
  • C-4 alkylated pyrazolo[3,4-d]pyrimidine nucleosides are prepare by reaction of the above mentioned suitably protected 4-chloropyrazolo[3,4- djpyrimidine nucleosides with carbanion nucleophiles.
  • a specific catalyst for thi alkylation reaction was found to be trimethylamine; these reactions either do not occur or proceed very slowly and in poor yield in the absence of trimethylamine.
  • Suitable carbanions include those derived from diethyl malonate, ethyl cyanoacetate, malononitrile, nitromethane, cyanide salts and the like. This procedure is also used to prepare C-6 alkylated purine ribosides. The initial C- alkylated products were deblocked and optionally further modified by hydrolysis and decarboxylation to afford the desired products.
  • the second general route for preparation of substituted pyrazolo[3,4- djpyrimidine nucleosides comprises coupling the esterified ribose (21) with vari substituted 4-amino or 4-hydrocarbylaminopyrazolo[3,4-d]pyrimidines.
  • the resulting products are then further modified or deblocked to afford the desired compounds.
  • the utility of this procedure is demonstrated in the Examples, by th preparation of 3-phenyl-4-(phenylamino)pyrazolo[3,4-d]pyrimidine 5'-modified ribosides from 3-phenyl-4-(phenylamino)pyrazolo[3,4-d]pyrimidine and various modified sugars.
  • halogenated pyrazolo[3,4]pyrimidine ribosides can be arylated using arylboronic acids and palladium catalysts as described for the pyrrolo[2,3-d]pyrimidines.
  • the base can be boronated and then coupled with an aryl halide. Further description of these procedures is set forth in the Examples.
  • One preferred method of the present invention is a novel procedure for preparing C-6 alkylated purine nucleosides and C-4 alkylated pyrazolo[3,4- djpyrimidine nucleosides from the 6-chloropurine and 4-chloropyrazolo[3,4- djpyrimidine nucleosides, respectively, using various carbanions (enolates, cyanide anion, etc.) and trimethylamine as a specific catalyst.
  • Another preferred method of the present invention is a process for prepa arylated bases and nucleosides by reaction of a halogenated pyrrolo[2,3- djpyrimidine or pyrazolo[3,4-d]pyrimidine with an aryl boronic acid in the prese of a palladium-phosphine catalyst.
  • the halogen atom of a brominated or preferably, iodinated pyrrolo[2,3-d]pyrimidine or pyrazolo[3,4- djpyrimidine base or nucleoside is replaced by an aryl moiety such as phenyl, substituted phenyl or a heteroaryl moiety such as furanyl.
  • a catalyst consisting metal such as palladium, complexed to an arylphosphine such as triphenylphosphine must be present as well as a base such as sodium carbona
  • the resulting arylated nucleosides are important examples of the present inven and this method is shorter and more versatile than alternative syntheses of aryl nucleosides.
  • Still another preferred method of the present invention is a process for preparing the previously unknown 3-iodo- and 3-chloropyrazolo[3,4-d]pyrimidi nucleoside by nonaqueous diazotization of 3-aminopyrazolo[3,4-d]pyrimidine nucleosides.
  • a suitably substituted 3- aminopyrazolo[3,4-d]pyrimidine nucleoside is diazotized by heating with an alk nitrite such as isoamyl nitrite in the presence of an iodine source (such as methylene iodide) resulting in replacement of the 3-amino moiety with an iodin atom.
  • an alk nitrite such as isoamyl nitrite
  • an iodine source such as methylene iodide
  • methylene iodide can be replaced by a chlorine source su as carbon tetrachloride resulting in replacement of the amino moiety by a chlori atom.
  • B' is lower alkyl or 1 to 3 carbon atoms optionally substituted with azido hydroxy, or lower alkenyl of 1 to 3 carbon atoms; D is bromo or iodo.
  • E is hydrog
  • F is chloro, mercapto, arylamino and G is hydrogen.
  • Certain intermediates useful in the preparation of certain preferred adenosine kinase inhibitor compounds comprise substituted pyrazolo[3,4- djpyrimidines of the formula:
  • aryl groups include heterocyclic aryl groups and monocyclic carbocyclic aryl groups including optionally substituted phenyl groups.
  • These preferred intermediates include the following compounds: 4-chloro-3-phenylpyrazolo[3,4-d]pyrimidine;
  • adenosine kinase inhibitors of the present invention may be used in t treatment of a variety of clinical situations where increasing local levels of adenosine are beneficial.
  • the compounds described herein and other adenosine kinase inhibitors are useful in treating conditions in which inflammatory processes are prevalent such as sepsis, arthritis, osteoarthritis, autoimmune disease, adult respiratory distress syndrome (ARDS), inflammatory bowel disease, necrotizing enterocoliti chronic obstructive pulmonary disease (COPD), psoriasis, conjunctivitis, iridocyditis, myositis, cerebritis, meningitis, dermitis, renal inflammation, ischemi reperfusion injury, peripheral vascular disease, atherosclerosis and other inflammatory disorders.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • COPD enterocoliti chronic obstructive pulmonary disease
  • psoriasis conjunctivitis, iridocyditis, myositis, cerebritis, meningitis, dermitis, renal inflammation, ischemi reperfusion injury, peripheral
  • Sepsis, septicemia and septic shock which involve an inflammatory response to a variety of injuries such as burns, pancreatinitis and infection, for example, by gram negative or gram positive bacteria, may be treate with an adenosine kinase inhibitor, such as the adenosine kinase inhibitors described herein.
  • an adenosine kinase inhibitor such as the adenosine kinase inhibitors described herein.
  • These compounds include pyrrolo[2,3- djpyrimidine nucleosides modified at the 5'-position or at other positions such th is less likely to serve as a substrate for phosphorylation enzymes and that, in contrast to 5-iodotubercidin (GP-1 -202), these compounds are unlikely to be phosphorylated at the 5'-position, incorporated into nucleotides or DNA, which cause toxicity to cells or animals.
  • GP-1 -202 5-iodotubercidin
  • Selected compounds such as GP-1 -238, were also evaluated to determi the potential for toxic hemodynamic effects or hypothermia associated with administration of adenosine kinase inhibitors. No effects were observed in conscious animals on blood pressure, heart rate or temperature with doses of inhibitor greatly in excess of that required to inhibit the cardiac adenosine kinas (Example C).
  • Example D the ability of selected adenosine kinase inhibitors (GP-l-272 and GP-1 -456) to inhibit neutrophil adherence to endotheii cells, an inflammatory response mediated at the cellular level was evaluated (Example D). Certain adenosine kinase inhibitors were found to exhibit anti- inflammatory activity in animal models of inflammation. The ability of particular adenosine kinase inhibitors to improve survival in a mouse model of endotoxic shock, both when administered immediately after E.
  • Coli LPS injection supports the ability of adenosine kinase inhibitors to prevent and treat septic conditions, including endotoxemia and endotoxic shock.
  • the efficacy of adenosine kinase inhibitors i treatment of sepsis is further demonstrated by the ability of particular adenosine kinase inhibitors to improve survival in another model of septic shock (Example The experiments described in Example H show that endotoxic mice treat with an adenosine kinase inhibitor have lower blood levels of tumor necrosis fa alpha (TNF- ⁇ ) compared with placebo treated mice.
  • TNF- ⁇ tumor necrosis fa alpha
  • Cytokines such as TNF- ⁇ have been suggested to be involved in many conditions including sepsis and septic shock (Zentella et al., Progress Clin. Biol. Research 367:9 (1990); Mathis et al., J. Clin. Invest. 81 :1925 (1988); Zanetti et al., J. Immunol. 148:1890 (1992); Creasey et al., Circ. Shock 33:82 (1991); Michie et al., N. Engl. J. Med. 318:148 (1988); Waage et al., Lancet_l(8529):355 (1987); Damas et al., Crit. Care Med.
  • Example H may indicate a broader therapeutic role for adenosine kinase inhibitors, including the novel compounds disclosed herein.
  • Example J describes the efficacy of GP-1-515 in the treatment endotoxic shock in pigs, as the treated animals did not develop the hypoxemia, hypercapnia and acidosis exhibited in the control animals.
  • plasma leakage An integral part of the inflammatory response involves an increase of vascular permeability to plasma proteins, herein termed "plasma leakage” or “vascular leakage”.
  • plasma leakage occurs when there is a change of the barrier properties of the vasculature in a tissue, and may be due to contraction of activat endothelial cells from each other leading to formation of a pore or to partial destruction of the vessel by cells participating in an aggressive immune respons
  • the suppression of vascular leakage by adenosine kinase inhibition is describe in Example K.
  • methods of the present invention may be useful in the treatment of conditions in which vascular leakage is present such as in inhalatio injury, the treatment of burns both locally at the injury site and in other organs su as lung (ARDS) and gut, or other edema induced by sepsis, burns or trauma.
  • vascular leakage such as in inhalatio injury
  • Example L Additional support for the use of adenosine kinase inhibitors in burn treatment is presented in Example L.
  • Bacterial infection is a common occurrenc during burn recovery.
  • the use of GP-1-515 was shown to significantly reduce bacterial translocation after a severe burn or pancreatitis.
  • Compounds of the invention are administered to the affected tissue at the rate of from 0.01 to 200 nmole/min/kg, preferably from 1 to 20 nmol/min/kg. Suc rates are easily maintained when these compounds are intravenously administered as discussed below. When other methods are used (e.g., oral administration), use of time-release preparations to control the rate of release of active ingredient may be preferred. These compounds are administered in a do of about 1 mg/kg/day to about 20mg/kg/day, preferably from about 3 mg/kg/day t about 8mg/kg/day and most preferrably about 5 mg/kg/day.
  • the compounds of the invention may b administered by a variety of means including orally, parenterally, by inhalation spray, sublingually, topically, or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the ter parenteral as used herein includes subcutaneous, intravenous, intramuscular, a intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters. Preferred for certain indications are methods of administration which allow rapid access to the tissue or organ being treated, such as intravenous injections for th treatment of myocardial infarction. When an organ outside a body is being treat perfusion is preferred.
  • compositions containing the active ingredient may be in form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to an method known to the art for the manufacture of pharmaceutical compositions an such compositions may contain one or more agents including those from the gr consisting of sweetening agents, flavoring agents, coloring agents and preservi agents, in order to provide a palatable preparation.
  • Tablets containing the activ ingredient in admixture with non-toxic pharmaceutically acceptable excipient w are suitable for manufacture of tablets are acceptable.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lacto calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestina tract and thereby provide a sustained action over a longer period. For example, time delay material such as glyceryl monostearate or glyceryl distearate alone o with a wax may be employed.
  • time delay material such as glyceryl monostearate or glyceryl distearate alone o with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsule wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraff or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraff or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl celluose, sodiu alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylen stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadeaethyleneoxycetanol), a condensation product of ethylen oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-o
  • the aqueous suspension may also contain one or more preservative such as ethyl of n-propyl p-hydroxybenzoate, or more coloring agent, one or more flavoring agent and one or more sweeteni agent, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a min oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as th set forth above, and flavoring agents may be added to provide a palpable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparatio of an aqueous suspension by the addition of water provide the active ingredient admixture with a dispersing or wetting agent, a suspending agent, and one or m preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • one or m preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
  • the pharmaceutical compositions of the invention may also be in the form oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and g tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters o partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art usi those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1 ,3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain 20 to 200 ⁇ moles of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions. It is preferred that pharmaceutical composition be prepared which provides easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion should contain from about 20 to about 50 ⁇ moles of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mUhr can occur.
  • formations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other tha the stomach. This is particularly advantageous with the compounds of formula (I) as such compounds are susceptible to acid hydrolysis.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprisin the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the ddPN ingredient such carriers as are known in the art to be appropriate.
  • Formations suitable for parenteral administration include aqueous and non aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formation isotonic with the bloo of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampouies and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of an adenosine kinase inhibitor compound.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in th art.
  • the method may be used following thrombolysis for coronary occlusion.
  • the compound would be given as a sterile injectable preparation with water or isotonic sodium chloride as the solvent.
  • the solution can be administered intravenously or directly into the coronary artery at the time of left heart catheterization or into a carotid artery.
  • the rate of administration could vary from 1 to 20 nmole/min/kg with, for example, an infusion volume of 30 mL/hr. Duration of therapy would typically be about 96 hours.
  • Capsules comprising adenosine kinase inhibitors suitable for oral administration according to the methods of the present invention may be prepared as follows: (1 ) for a 10,000 capsule preparation: 1500g of adenosine kinase inhibitor is blended with other ingredients (as described above) and filled into capsules which are suitable for administration depending on dose, from about 4 capsules per day (1 per 6 hours) to about 8 capsules per day (2 capsules per 6 hours), to an adult human.
  • the compounds of this invention and their preparation can be understoo further by the examples which illustrate some of the processes by which these compounds are prepared. These examples should not however be construed specifically limiting the invention and variations of the invention, now known or l developed, are considered to fall within the scope of the present invention as hereinafter claimed.
  • Example 1 Preparation of 5'-Azido-5'-deoxy-2'. 3'-Q-(1-methylethylidene) inosi This material was prepared by tosylation of 2', 3'-(1-methyl- ethylidene)inosine and subsequent reaction with sodium azide in DMSO as described by Hampton, A.; J. Org. Chem., 1968, 11:1220.
  • EXAMPLE 22 Preparation of 6-Chloro-9-[5-deoxy-2.3-Q-(1-methylethylidene)-1- D-ribofuranosyllpurine A solution of the blocked 5'-deoxyinosine (1.4 g, 4.8 mmol), tetraethylammonium chloride (1.9 g, 11.5 mmol), diethylaniline (1.2 mL, 7.2 mm and phosphorous oxychloride (3.35 mL, 36 mmol) in CH3CN (24 mL) was reflux for 10 minutes then evaporated. The residue was dissolved in CH2CI2, washed with water, KHCO3 solution, water and dried. The solution was filtered and evaporated to give 860 mg (65% yield) of title compound as a yellow oil.
  • EXAMPLE 23 General Procedure for Preparation of N£ substituted 5'- deoxyadenosines
  • the above-identified compound may be prepared as described: Ikshara, Kaneko, M.; Sagi, M.; Tetrahedron. 1970, 26:5757.
  • N ⁇ -formyl derivative was deformylated by slurrying in MeOH, adding saturated methanolic ammonia (80 mL) and warming until homogenous. After 1 minutes the solution was evaporated, the residue recrystallized from EtOH and dried to give the title compound; 0.900 g (60% yield); m.p. 166-168°C.
  • Example 26 The isopropylidene diazide of Example 26 (1.00 g, 3.15 mmol) was deblocked as described under Example 4 and recrystallized from H2O; 760 mg (85% yield); m.p. 128-130°.
  • Example 27 The diazide of Example 27 (0.660 g, 2.0 mmol) was hydrogenated as described under Example 15 and recrystallized from EtOH to give, after drying, 4 mg of the free base (61% yield). This material was further purified by conversion the formate salt (HC ⁇ 2H/EtOH/Et2 ⁇ ); m.p. 98°C(d).
  • Example 30 To a cold (0°C) solution of the alcohol (Example 30) (6.0 g, 0.015 mol) in d pyridine (40 mL) was added with stirring, p-toluenesuifonyl chloride (6.96 g, 0.36 mol). The solution was sealed and stored at 0-10°C for 72 hours then poured int cold H2O (30 mL). The solid was collected by filtration and rinsed 3x with H2O.
  • p-toluenesuifonyl chloride 6.96 g, 0.36 mol
  • EXAMPLE 33 Preparation of 6-(N-lndolinyl)-9- ( 5-methylamino-5-deoxy-1 -B-D- ribofuranosyDpurine Hvdrochloride To 40% aqueous methylamine (40 mL) was added the tosylate (Example 32) (2.0 g, 3.8 mmol) and sufficient MeOH to give a clear solution. The solution was stirred for one week then concentrated. The residue was coevaporated 3x with MeOH then recrystallized from MeOH to give the free base, 0.310 g (21% yield). A portion of this material was converted to the hydrochloride salt, m.p. 17 172°.
  • EXAMPLE 39 Preparation of 2-Amino-4-chloro-7H-Pyrrolo.2.3-dlpyrimidine
  • the above-identified compound was prepared as described: Pudlo, J.; Nassiri, M.; Kern, E.; Wotrlng, L.; Drach, J.; Townsend, L; J. Med. Chem.. 1990, 3 1984.
  • EXAMPLE 40 Preparation of 2-Amino-4-chloro-7H-pyrrolo[2.3-dlpyrimidine The above-identified compound was prepared as described. Seela, F.; Stiker, H.; Driller, H.; Binding, N.; Liebigs Ann. Chem.. 1987, 15.
  • This compound may also be prepared as described: Tollman et al., J. Am Chem. Soc. 1969, 91 :2102.
  • EXAMPLE 46 Preparation of 5-O-Methyl-D-ribofuranose The above-identified compound was prepared as described: Snyder, J.; Serianni, A.; Carbohydrate Research. 1987, 163:169.
  • EXAMPLE 48 Preparation of 5-Deoxy-2.3-Q-(1-methylethylidene)-D-ribofuranos 5-Deoxy-D-ribofuranose (8.g, 60 mmole) was dissolved in DMF (25 mL) a to the solution was added dimethoxypropane (10 mL) and p-toluenesulfonic acid (150 mg). The reaction was stirred overnight then neutralized with OH" resin. Th mixture was filtered, concentrated and the residue chromatographed on silica ge Collected like fractions and evaporated to yield 4.1 g (39% yield) of viscous liqui
  • EXAMPLE 50 5-Azido-5-deoxy-1-Q-methyl-2.3-0-(1-methylethylidene)-D- ribofuranoside
  • Example 51 The crude 5-azido-5-deoxyribose (Example 51 ) was dissolved in DMF (1 mL) and treated with 2,2-dimethoxypropane (10 mL) and p-toluenesulfonic aci (100 mg). The solution was stirred at room temperature for 20 hours then evaporated. The residue was chromatographed. The appropriate fractions we pooled and evaporated to obtain the title compound, yield 2.4 g (56% yield).
  • the sugar aldehyde from Example 53 (100 mmol) was dissolved in THF treated with methyl magnesium bromide (100 mmol). After 2 hours of stirring at room temperature, a saturated solution of ammonium chloride in water (180 m was added. The organic layer was separated and the aqueous layer was extra with ether (2 x 100 mL). The combined organic layers were dried and evapora to obtain an oily product whose NMR was consistent with methyl-6-deoxy-2,3- isopropylidene-D-allofuranoside. The crude product was dissolved in pyridine mL) and treated with benzoic anhydride (120 mmole). After stirring for 18 hours methanol (2 mL) was added and the reaction mixture was evaporated.
  • the resi was dissolved in ethyl acetate (300 mL) and washed with water, saturated bicarbonate solution, and brine. The organic layer was dried and evaporated t obtain a glassy product which was purified by chromatography. Identity of the product was confirmed by IR and NMR spectroscopy.
  • the intermediate protecte sugar was heated with aqueous sulfuric acid solution (0.01 N in water, 300 mL) 80°C for 2 hours and neutralized with resin. The aqueous layer was separated evaporated to obtain the title compound as a sticky mass. The product was confirmed by NMR and used in the next step without further purification.
  • the benzoylated sugar (Example 54) was dissolved in a mixture of dry D (20 mL), 2,2-dimethoxypropane (20 mL) and p-toluenesulfonic acid (200 mg) a stirred at room temperature. After 2 hours the reaction mixture was neutralized strongly basic ion exchange resin and the resin removed by filtration and wash The combined washings and filtrate were evaporated and the residue was purif by chromatography. The pure product obtained was a glassy solid.
  • the minor product, Rf 0.7, (10%) was identified as 6-deoxy-1 methyl-2,3-0-(1-methylethylidene)-D-allofuranoside.
  • This compound may be prepared by t-butyldimethylsilylation of the 6- hydroxy sugar, using t-butyldimethylsilyl chloride and imidazole in DMF.
  • EXAMPLE 62 Preparation of 5-deoxy-1-methyl-2.3-Q- ( 1-methylethylidene)-6-p- toluenesulfonyl-D-allofuranoside To an ice-cold solution of the hydroxy sugar Example 60, (3.69 g) in pyridin
  • the protected nucleoside was deblocked by dissolving in 90% trifluoroaceti acid and stirring for 2 hours. The solvent was evaporated and chased with methanol (3x). The product was crystallized from EtOH.
  • the insoluble material was filtered and the pH of the filtrate was adjusted to 5.5 with dilute HCl.
  • the solution was refiltered and lyophilized to obtai a hygroscopic solid, whose NMR was compatible with the structure.
  • EXAMPLE 114 Preparation of 5-lodo-7- ( 5-deoxy-1-B-D-ribofuranosyl)pyrrolo.2.3- d1pyrimidin-4(3H)-thione
  • Example 122-124 The above-identified compounds were prepared as described in Example 122-124 from the 4-amino- or 4-arylamino-5-iodo-7-(5-deoxy-1- ⁇ -D- ribofuranosyl)pyrrolo[2,3-d]pyrimidine and an arylboronic acid.
  • Example 127 The 4-chloro compound, Example 127, was heated in a steel bomb with methanolic ammonia at 120°C for 12 hours followed by the usual work up (see Example 85). A white crystalline product was obtained; m.p. 206-208°C.
  • EXAMPLES 140-144 General Procedure for the Preparation of 5-Amino-3-aryl-4- cvanopyrazoles The above-identified compounds were prepared from the corresponding ar thiomorpholides (Examples 135-139) following the general procedure described: Tominaga, Y.,; et al.; J. Heterocyclic Chem.. 1990, 27:647.
  • a mixture of the 5-amino-3-aryl-4-carboxamidopyrazole and formamide (5 mL/g) was refluxed at 190°-200°C for 2 hours, cooled and diluted with H2O. The solid was collected by filtration and dried. Further purification was effected by dissolving the compound in dilute sodium hydroxide, followed by charcoal treatment and precipitation with acetic acid.
  • EXAMPLE 165 Preparation of 3-Bromo-1-(2.3.5-Q-tribenzovl-1- ⁇ -D- ribofuranosyl)pyrazolo[3.4-d)pvrimidin-4-one The above-identified compound was prepared as described: Cottam, H.;
  • EXAMPLE 166 Preparation of 3-Substituted-4-chloro-l-(2.3.5.-Q-tribenzovl-1- ⁇ - ribofuranosvl)pvrazolof3.4-d]pvrimidin-4-ones
  • the above-identified compounds may be prepared from the correspondin pyrazolo[3,4-d]-pyrimidones by a procedure analogous to the one described in Example 2.
  • EXAMPLE 171 Preparation of 3-Bromo-1-r2.3-Q-(1-methylethylidene)-1- ⁇ -D- ribofuranosyllpyrazolo[3.4-d]pyrimidin-4-one Crude 3-bromoallopurinol riboside (prepared from 33.0 g of tribenzoate and
  • Example 83 NaOMe/MeOH (Example 83) was added to a 5°C solution of 1 M ethanolic HCl (6.5 mL) and dimethoxypropane (20 mL) in 1.1 L of acetone. The mixture was stirred 45 minutes. Na2C ⁇ 3 (5.0 g) and concentrated NH4OH (5 mL) were added and the mixture pH reached 6-7. The reaction was filtered and evaporated. The residual solid was dissolved in 300 mL of boiling EtOH and the solution concentrated. The solution was chilled overnight and the solid collected by filtration. After drying (50°C), 16.7 g (86%) of the title compound were obtained; m.p. 221-224°C.
  • EXAMPLE 172 Preparation of 3-Bromo-1-[2.3-0-(1-methylethylidene)-5-0-(4- methylbenzenesulfonyl)-1- ⁇ -D-ribofuranosyllpyrazolo[3.4-dlpyrimidin-4-one
  • isopropylidene alcohol (Example 171) (3.0 g, 7.74 mmol) in pyridine (18 mL) at 0°C was added p-toluenesulfonyl chloride (1.77 g, 9.30 mmol). The reaction was held at 0°C for 3 hours then poured into 160 mL of cold
  • EXAMPLE 176 Preparation of 3-lodo-1--2.3-0-(1-methylethylidene)-5-Q-(4- methylbenzenesulfonyl)-1- ⁇ -D-ribofuranosyllpyrazolo-[3.4-d]pyrimidin-4-one
  • Example 173 or 177 The above identified compounds were prepared by a procedure analogous to the one described for Example 2 from the pyrimidin-4-one (Example 173 or 177). The title compounds were obtained as unstable yellow oils and used immediately in the next step.
  • the reactions using amines were worked up in the following manner.
  • the reaction mixture was evaporated, the residue dissolved in CH2CI2 and the solution washed with aqueous NaHC ⁇ 3, H2O and dried .
  • Concentration of the CH2CI2 solution and chromatography of the residue gave the purified isopropylidene N4- substituted compounds.
  • the isopropylidene 4-amino compounds were isolated by evaporating the reaction mixture and recrystallizing the residue from EtOH.
  • EXAMPLE 187 Preparation of 1.2.3-0-Triacetyl-5-azido-5-deoxy-D-ribofuranoside To a cooled solution of 5-azido-5-deoxyribose (6.2 g, 0.035 mole) (Example 51) in 10 mL of pyridine was added acetic anhydride (18 mL) and the mixture stirred for 24 hours. The mixture was concentrated, the residue dissolved in CH2CI2 and the solution washed with 5% NaHC03. The organic layer was then washed with 0.5 N H2SO4, dried and evaporated. The residue was dissolved in CH2CI2, filtered through a plug of silica gel and the filtrate concentrated to afford the title compound, 9.0 g (98% yield) as a semisolid mixture of ⁇ and ⁇ isomers.
  • EXAMPLE 204 General Procedure for the Preparation of 3-Substituted 1-(5-azido- 5-deoxy-2.3-Q-diacetyl-1- ⁇ -D-ribo-furanosyl)-4-chloropyrazolof3.4- d)pyrimidines.5'-Deoxy Analogs and Protected 5'-Hvdroxy Analogs
  • the above-identified compounds were prepared from the 5'-azides (Examples 205-221) by catalytic hydrogenation as described in Examples 15-20 (method A) or triphenylphosphine followed by ammonium hydroxide as described in Examples 82-83 (method B).
  • the salts were prepared by standard methods.
  • the diester (Examples 232-233) was dissolved in aqueous ethanolic sodium hydroxide and heated. The solution was neutralized with acetic acid, 0 evaporated, extracted with hot ethanol and the extract then evaporated and Ik recrystallized or chromatographed. The appropriate fractions were combined and evaporated to yield the title compounds.
  • Example A A METHOD OF MEASURING THE INHIBITION OF ADENOSINE KINASE ACTIVITY
  • Inhibition of enzyme activity was determined using a 0.1 mL assay mixture containing 50 mM Tris-maleate, pH 7.0, 0.1% (w/v) BSA, 1 mM ATP, 1 mM MgCl2, 0.5 ⁇ M [U- 14 C] adenosine (500 mCi/mmol) and 0.1 ⁇ g of purified pig heart adenosine kinase. Different concentrations of the test compounds were incubated in the assay mixture for 20 min. at 37 °C.
  • A1 receptor binding affinity was determined using 0.5 mL 5 mixture containing 50 mM Tris HCl, pH 7.4, 1 nM [ 3 H]cyclohexyladenosine (CHA) and 0.5 mg of neuronal membrane incubated with different concentrations of the test compound for 60 min at 37 °C. The reaction was stopped and unbound [ 3 H]CHA removed by rapid filtration through Whatman GF/B filters. The filter paper were then solubilized and bound [ 3 H]CHA determined by scintillation counting.
  • CHA [ 3 H]cyclohexyladenosine
  • i o Inhibition of adenosine deaminase activity was determined spectrophotometrically using a 1 mL assay mixture containing 50 mM potassium phosphate, pH 7.0, 1 mM ADP, 2.5 mM alpha-ketoglutarate, 15 units glutamic dehydrogenase, 0.125 mM NADH, 80 ⁇ M adenosine and 0.002 units of calf intestinal mucosa adenosine deaminase. Different concentrations of the test
  • the compound GP-1-515 was found to be much less potent in the A1 receptor assay and in the adenosine deaminase inhibition assay, having an IC50 greater than 100 ⁇ M in the A1 receptor assay and an IC50 greater than 1000 ⁇ M in the adenosine deaminase inhibition assay.
  • adenosine kinase inhibition was determined from the amount of incorporation of radioisotope from adenosine into the adenylates (AMP, ADP and ATP) in the presence of adenosine deaminase inhibition.
  • endothelial cells from bovine heart were incubated for 60 min. with 20 ⁇ M 2'- deoxycoformycin, a potent adenosine deaminase inhibitor. Different concentrations of the test compounds were then added to the cells and incubated for 15 min. after which 5 ⁇ M [ 3 H]adenosine was added and the cells incubated for a further 15 min. The media was then discarded and the cells were treated with 50 ⁇ l 0.4 M perchloric acid, centrifuged and the supernatants neutralized with 100 ⁇ l alanine: freon (1:4). Radioisotope-labeled adenylates were separated by TLC on PEI cellulose plates developed in methanol: water (1 :1) and incorporation of 3 H determined by scintillation counting.
  • the compounds designated GP-1-515, GP-1 -683 and GP-1-665 were shown to have an IC50 of 9 nM, 73 nM and 4.5 nM, respectively, in the adenosine kinase inhibition assay in intact cells.
  • Example C EFFECT OF ADENOSINE KINASE INHIBITION ON ACUTE IN. HEMODY ⁇ AMICS IN THE RAT
  • GP-1 -238 The ability of the adenosine kinase inhibitor GP-1 -238 to show effects on blood pressure, heart rate or body temperature was compared in anesthetized and conscious rats. Sprague Dawley rats were anesthetized with pentobarbital and catheterized in the jugular vein and carotid artery. GP-1 -238 (0.1-5 mg/kg/min) was infused intravenously in stepwise increments (0.2 mLJmin x 5 minutes). The experiments in conscious rats were conducted in the same manner after rats had been catheterized and allowed to recover for 2 days following surgery. In conscious rats, in contrast to anesthetized animals, no hemodynamic effects were seen at doses which completely inhibited adenosine kinase jn vivo See Figure 1.
  • Example D INHIBITION OF NEUTROPHIL ADHERENCE TO FIBROBLASTS OR ENDOTHELIAL CELLS
  • adenosine kinase inhibitor to affect neutrophil adherence to fibroblasts and endothelial cells was evaluated in a cell culture model. Cultures of human dermal fibroblasts or human umbilical vein endothelial cells were washed and then incubated for 2 hours at 37 °C in a 5% CO2 atmosphere in fresh medium containing different concentrations of the adenosine kinase inhibitors GP-1 -272 and GP-1 -456. These incubations were carried out in the presence of fMLP- stimulated human neutrophils isolated from whole blood (1.25 x 106/mL) with or without adenosine deaminase (0.125 U/mL).
  • Example E IMPROVED SURVIVAL IN ENDOTOXEMIA IN ADENOSINE KINASE INHIBITOR-TREATED MICE
  • An adenosine kinase inhibitor (GP-1-515) was used to increase endogenous adenosine production In vivo.
  • Figure 9 shows the results of an experiment in which Balb/C mice received an intravenous injection of 900 ug of E. coli LPS (Sigma Chemical Co., St Louis, MO) followed immediately by an intravenous injection of an adenosine kinase inhibitor (GP-1-515) or carrier (10 animals per group).
  • Example E intravenous treatment with an adenosine kinase inhibitor improves survival of mice if administered immediately after intravenous injection with LPS.
  • an adenosine kinase inhibitor (GP-1-515) protects animals against endotoxemia if administered prophylactically.
  • 25-30 gram male Balb/C mice received oral GP-1-515 (5 mg/kg in water) or vehicle by gavage.
  • the animals received an intravenous injection of 700 ug of E. coli LPS (Sigma Chemical Co.).
  • 50% of mice in the adenosine kinase inhibitor-treated group survived for 2 days, while none of animals in the vehicle treated group survived for that time period (data not shown).
  • Example G EFFICACY OF AN ADENOSINE KINASE INHIBITOR IN MODEL OF CHRONIC SEPSIS. CECAL LIGATION AND PUNCTURE
  • Cecal ligation and puncture is a model of bacterial peritonitis and septic shock which mimics systemic infections in humans.
  • male CD rats were fasted overnight and treated orally with either GP-1-515 (5 mg/kg) or vehicle by gavage. Two hours later, animals were anesthetized with ether and the anterior abdominal wall was shaved. A midline incision was made and the cecum was exteriorized and ligated with 3-0 silk suture near the ilial-cecal junction without causing bowel obstruction. The cecum was punctured twice on th anti-mesenteric side using a yellow tip disposable pipette tip (Fisher, Tustin, CA) and squeezed to ensure patency.
  • GP-1-515 5 mg/kg
  • CA yellow tip disposable pipette tip
  • mice received an intravenous injection of E. coli LPS (900 ug/animal) (Sigma Chemical Co.) followed immediately by a second injection with 0.1 mg/kg of GP-1-515 or vehicle.
  • E. coli LPS 900 ug/animal
  • 8SPT the adenosine receptor antagonist 8SPT.
  • blood was obtained from ether 5 anesthetized animals by intracardiac puncture using a heparinized syringe. Blood samples were chilled on ice, centrifuged at 5000 rpm in a microcentrifuge for 5 minutes, and the plasma removed.
  • TNF- ⁇ levels in the plasma were assayed by ELISA according to the instructions provided by the manufacturer (Endogen, Cambridge, MA).
  • the adenosine kinase inhibitor, GP-1- ⁇ o 515 significantly decreased plasma TNF- ⁇ levels (p ⁇ 0.01). The decrease was prevented in animals pre-treated with 200 mg/kg i.p. of the adenosine receptor antagonist 8SPT 30 minutes prior to injection with LPS and GP-1-515.
  • Example I EFFECTS OF THE ADENOSINE KINASE INHIBITOR. GP-1-456.
  • GP-1-456 The adenosine kinase inhibitor, GP-1-456, was examined for anti- inflammatory activity in adjuvant arthritis in rats.
  • Lewis rats received a single subcutaneous tail injection of 0.75 mg Mycobacterium butyricum mixed in paraffin oil on day 0.
  • the rats were treated with 3 mg/kg GP-1-456 p.o., or a vehicle control
  • mice Male or female Yucatan miniature pigs (20-27 kg) were pre-medicated with xylazine (550 mg i.m.), ketamine (150 mg i.m.), and atropine (1 mg i.m.). The animals were intubated, administered 10 mg/kg of pentobarbital intravenously, an
  • a pentobarbital infusion was maintained at 10 mg/kg/hr.
  • the pigs were ventilated with 30% O2 usi a Harvard large animal respirator at 7-10 breaths/min in order to achieve a blood p of approximately 7.45-7.50.
  • a bolus of 4 mg of Pancuronium bromide was given to inhibit muscle contraction in response to the cautery and the animals were hydrate with a continuous infusion of saline at 60-80 cc/hr.
  • a left thoracotomy was performe in the third intercostal space and the pulmonary artery, carotid artery, external jugul vein were cannulated with PE-190 tubing.
  • a line was also placed in the left atrium and a catheter tipped micromanometer was inserted into the left ventricle via an apical stab wound.
  • a transit-time flow probe was placed on the pulmonary artery. Pressure readings were obtained using a Statham pressure transducer connected a Gould strip chart recorder. Heparinized arterial blood samples for blood gases were obtained through the carotid arterial catheter. Drugs and endotoxin were infused through the external jugular catheter.
  • GP-1-515 0.3 ⁇ g/kg/min
  • LPS lipopolysaccharide
  • the animals continued to receive GP-1-515 or vehicle for 4 additional hours and were ventilated with a fixed tidal volume and Fi ⁇ 2.
  • the most prominent findings pertaine to gas exchange and pulmonary function, with marked protection observed in the GP-1-515-treated animals. Control animals developed severe hypoxemia, hypercapnia, and acidosis.
  • Carrageenan and histamine induced plasma leakage in rat skin since the plasma content was significantly higher in skin sites injected with these agents compared to PBS-injected sites.
  • Treatment with GP-1 -792 (5 mg/kg p.o. 1 hr prior to experiment) significantly inhibited carrageenan- and histamine-induced plasma leakage by 47+5 and 51+5%, respectively ( Figure 14). Since histamine acts directly on endothelial cells, the protective effect of GP-1 -792 can be mediated by an effect on endothelial cells in addition to a decrease in neutrophil accumulation 5 in the tissue in this model as occurs with carrageenan.
  • Example L EFFECT OF AN ADENOSINE KINASE INHIBITOR IN A BURN MODEL
  • mice 15 mg/kg.
  • the animals were administered a second injection of GP-1-515 (0.1 mg/kg) or vehicle i.p. 6 hours after the burn. Animals were fasted for 4 hours befor the burn and for 24 hours thereafter. After 48 hours, the animals were sacrificed b cervical dislocation and the abdomen was opened using aseptic techniques. Mesenteric lymph nodes were harvested and weighed in sterile bags,
  • mice 20 homogenized in Trypticate Soy Broth (BBL, Becton Dickinson Microbiology System, Cockeysville, MD). Serial dilutions of the homogenate were plated on heart-brain-infusion agar plates (BBL, Becton Dickinson) at 37 °C and the presence or absence of bacterial colonies was determined 48 hours later. In experiments involving approximately 120 animals, 52% of control mice had

Abstract

Composés nouveaux qui inhibent sélectivement l'adénosine kinase et procédés de préparation desdits inhibiteurs. D'autres procédés permettant de traiter différents troubles qu'on peut atténuer grâce à des concentrations locales accrues d'adénosine en recourant à ces inhibiteurs d'adénosine kinase sont également décrits.
PCT/US1994/001340 1993-02-03 1994-02-03 Inhibiteurs de l'adenosine kinase Ceased WO1994017803A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP94909558A EP0682519A4 (fr) 1993-02-03 1994-02-03 Inhibiteurs de l'adenosine kinase.
AU62365/94A AU6236594A (en) 1993-02-03 1994-02-03 Adenosine kinase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1419093A 1993-02-03 1993-02-03
US08/014,190 1993-02-03

Publications (2)

Publication Number Publication Date
WO1994017803A1 WO1994017803A1 (fr) 1994-08-18
WO1994017803A9 true WO1994017803A9 (fr) 1994-09-29

Family

ID=21764031

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/001340 Ceased WO1994017803A1 (fr) 1993-02-03 1994-02-03 Inhibiteurs de l'adenosine kinase

Country Status (4)

Country Link
EP (1) EP0682519A4 (fr)
AU (1) AU6236594A (fr)
IL (1) IL108523A0 (fr)
WO (1) WO1994017803A1 (fr)

Families Citing this family (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674998A (en) * 1989-09-15 1997-10-07 Gensia Inc. C-4' modified adenosine kinase inhibitors
US5726302A (en) * 1989-09-15 1998-03-10 Gensia Inc. Water soluble adenosine kinase inhibitors
US5763596A (en) * 1989-09-15 1998-06-09 Metabasis Therapeutics, Inc. C-4' modified adenosine kinase inhibitors
US5763597A (en) * 1989-09-15 1998-06-09 Metabasis Therapeutics, Inc. Orally active adenosine kinase inhibitors
US5795977A (en) * 1989-09-15 1998-08-18 Metabasis Therapeutics, Inc. Water soluble adenosine kinase inhibitors
US5864033A (en) * 1989-09-15 1999-01-26 Metabasis Therapeutics, Inc. Adenosine kinase inhibitors
US5721356A (en) * 1989-09-15 1998-02-24 Gensia, Inc. Orally active adenosine kinase inhibitors
DK0682027T3 (da) * 1994-05-03 1998-05-04 Ciba Geigy Ag Pyrrolopyrimidinderivater med antiproliferativ virkning
US6395733B1 (en) 1995-06-07 2002-05-28 Pfizer Inc Heterocyclic ring-fused pyrimidine derivatives
US6143749A (en) * 1995-06-07 2000-11-07 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
US5665721A (en) * 1995-06-07 1997-09-09 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
EP0840740B1 (fr) * 1995-07-11 2002-05-02 AstraZeneca AB Nouveaux inhibiteurs de l'agregation plaquettaire
JP4275733B2 (ja) * 1996-01-23 2009-06-10 ノバルティス アクチエンゲゼルシャフト ピロロピリミジンおよびその製造法
JP4255138B2 (ja) * 1996-05-24 2009-04-15 湧永製薬株式会社 脳疾患治療剤
WO1998001459A1 (fr) * 1996-07-05 1998-01-15 Novo Nordisk A/S Nouveaux derives de n-alcoxyadenine inhibant la cytokine
US5824657A (en) * 1997-03-18 1998-10-20 Cubist Pharmaceuticals, Inc. Aminoacyl sulfamides for the treatment of hyperproliferative disorders
US7863444B2 (en) 1997-03-19 2011-01-04 Abbott Laboratories 4-aminopyrrolopyrimidines as kinase inhibitors
EP0870502A3 (fr) * 1997-04-10 2001-04-04 Kyowa Hakko Kogyo Co., Ltd. Utilisation d'inhibiteurs de l'assimilation d'adénosine pour la fabrication d'un médicament pour le traitement de la pancréatite
US6713474B2 (en) 1998-09-18 2004-03-30 Abbott Gmbh & Co. Kg Pyrrolopyrimidines as therapeutic agents
JP2002526500A (ja) * 1998-09-18 2002-08-20 ビーエーエスエフ アクチェンゲゼルシャフト プロテインキナーゼ阻害剤としてのピロロピリミジン
TWI229674B (en) 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
PT1212327E (pt) 1999-09-17 2004-01-30 Abbott Gmbh & Co Kg Pirazolopirimidinas como agentes terapeuticos
US7071199B1 (en) 1999-09-17 2006-07-04 Abbott Gmbh & Cco. Kg Kinase inhibitors as therapeutic agents
MXPA02005959A (es) * 1999-12-16 2003-10-14 Alcon Inc Inhibidores de adenosina cinasa para el tratamiento del nervio optico y el bano retiniano.
WO2001072751A1 (fr) * 2000-03-29 2001-10-04 Knoll Gesellschaft Mit Beschraenkter Haftung Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases
GB0100623D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds IV
GB0100622D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds V111
DE10238722A1 (de) 2002-08-23 2004-03-11 Bayer Ag Selektive Phosphodiesterase 9A-Inhibitoren als Arzneimittel zur Verbesserung kognitiver Prozesse
DE10238724A1 (de) 2002-08-23 2004-03-04 Bayer Ag Alkyl-substituierte Pyrazolpyrimidine
WO2004092177A1 (fr) 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolopyrazines et procedes de preparation et d'utilisation ce celles-ci
EP1615930A2 (fr) 2003-04-09 2006-01-18 Biogen Idec MA, Inc. Triazolotriazines et pyrazolotriazines et leurs procedes de fabrication et d'utilisation
DE602004018637D1 (de) 2003-04-09 2009-02-05 Biogen Idec Inc A2a-adenosinrezeptorantagonisten
AR049384A1 (es) 2004-05-24 2006-07-26 Glaxo Group Ltd Derivados de purina
JP2008520744A (ja) * 2004-11-19 2008-06-19 ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア 抗炎症性ピラゾロピリミジン
GB0514809D0 (en) 2005-07-19 2005-08-24 Glaxo Group Ltd Compounds
KR20130087054A (ko) 2006-04-04 2013-08-05 더 리젠트스 오브 더 유니이버시티 오브 캘리포니아 키나제 길항물질
EP2574616A3 (fr) * 2007-08-02 2013-09-04 Southern Research Institute Adénosynes 5 '-substituées, leur préparation et leur utilisation comme inhibiteurs de la décarboxylase s-adénosylméthionine
WO2009046448A1 (fr) 2007-10-04 2009-04-09 Intellikine, Inc. Entités chimiques et leurs utilisations thérapeutiques
PE20091211A1 (es) 2007-11-30 2009-09-14 Boehringer Ingelheim Int Derivados de pirazolopirimidina como moduladores de pde9a
MX358640B (es) 2008-01-04 2018-08-29 Intellikine Llc Isoquinolin-1 (2h) -onas y tieno [2,3-d]pirimidin-4(3h) -onas substituidas, y metodos de uso de las mismas.
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
TR201815961T4 (tr) * 2008-01-18 2018-11-21 Inst Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Yeni sitostatik 7-deazapürin nükleozidleri.
JP5547099B2 (ja) 2008-03-14 2014-07-09 インテリカイン， エルエルシー キナーゼ阻害剤および使用方法
WO2009114874A2 (fr) 2008-03-14 2009-09-17 Intellikine, Inc. Inhibiteurs de kinases (benzothiazole) et procédés d’utilisation associés
UA105362C2 (en) 2008-04-02 2014-05-12 Бьорингер Ингельхайм Интернациональ Гмбх 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators
WO2010006072A2 (fr) 2008-07-08 2010-01-14 The Regents Of The University Of California Modulateurs de mtor et leurs utilisations
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
GB0815968D0 (en) * 2008-09-03 2008-10-08 Angeletti P Ist Richerche Bio Antiviral agents
CA2736304A1 (fr) 2008-09-08 2010-03-11 Boehringer Ingelheim International Gmbh Pyrazolopyrimidines et leur utilisation pour le traitement de troubles du snc
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
JP5819195B2 (ja) 2008-10-16 2015-11-18 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 融合環ヘテロアリールキナーゼ阻害剤
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
EP2623104A1 (fr) * 2009-03-20 2013-08-07 Alios Biopharma, Inc. Analogues nucléosidiques et nucléotidiques substitués
GEP20146098B (en) 2009-03-31 2014-05-27 Boehringer Ingelheim Int 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their usage as pde9a modulators
JP5721275B2 (ja) * 2009-04-22 2015-05-20 インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエス シーアール， ブイ．ブイ．アイ． 治療的使用のための新規７−デアザプリンヌクレオシド
JP5789252B2 (ja) 2009-05-07 2015-10-07 インテリカイン， エルエルシー 複素環式化合物およびその使用
WO2011047384A2 (fr) 2009-10-16 2011-04-21 The Regents Of The University Of California Procédés d'inhibition de l'activité ire1
EP2571357B1 (fr) 2010-05-21 2016-07-06 Infinity Pharmaceuticals, Inc. Composés chimiques, compositions et procédés pour modulation de kinases
MX344770B (es) 2010-08-12 2017-01-06 Boehringer Ingelheim Int Gmbh * Derivados de 6-cicloalquil-1,5-dihidro-pirazolo (3,4-d) pirimidin-4-onas y su uso como inhibidores de pde9a.
CA2810928A1 (fr) 2010-09-22 2012-03-29 Alios Biopharma, Inc. Analogues nucleotidiques substitues
CN103298474B (zh) 2010-11-10 2016-06-29 无限药品股份有限公司 杂环化合物及其用途
TWI546305B (zh) 2011-01-10 2016-08-21 英菲尼提製藥股份有限公司 製備異喹啉酮之方法及異喹啉酮之固體形式
US8809345B2 (en) 2011-02-15 2014-08-19 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
EP2678018A4 (fr) 2011-02-23 2015-09-30 Intellikine Llc Combinaison d'inhibiteurs des kinases et utilisations associées
WO2013012918A1 (fr) 2011-07-19 2013-01-24 Infinity Pharmaceuticals Inc. Composés hétérocycliques et leurs utilisations
AU2012284088B2 (en) 2011-07-19 2015-10-08 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
CA2846431A1 (fr) 2011-08-29 2013-03-07 Infinity Pharmaceuticals Inc. Composes heterocycliques et leurs utilisations
MX370814B (es) 2011-09-02 2020-01-08 Univ California Pirazolo[3,4-d]pirimidinas sustituidas y usos de las mismas.
CA2860234A1 (fr) 2011-12-22 2013-06-27 Alios Biopharma, Inc. Analogues de nucleotide phosphorothioate substitue
HK1206362A1 (zh) 2012-03-21 2016-01-08 Alios Biopharma, Inc. 硫代氨基磷酸酯核苷酸前藥的固體形式
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
RU2015115631A (ru) 2012-09-26 2016-11-20 Дзе Риджентс Оф Дзе Юниверсити Оф Калифорния Модулирование ire1
CN105102000B (zh) 2012-11-01 2021-10-22 无限药品公司 使用pi3激酶亚型调节剂的癌症疗法
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US9724354B2 (en) 2013-03-22 2017-08-08 Millennium Pharmaceuticals, Inc. Combination of catalytic mTORC1/2 inhibitors and selective inhibitors of Aurora A kinase
MX389256B (es) 2013-10-04 2025-03-20 Infinity Pharmaceuticals Inc Compuestos heterociclicos y usos de los mismos.
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
EA201691872A1 (ru) 2014-03-19 2017-04-28 Инфинити Фармасьютикалз, Инк. Гетероциклические соединения для применения в лечении pi3k-гамма-опосредованных расстройств
WO2015160975A2 (fr) 2014-04-16 2015-10-22 Infinity Pharmaceuticals, Inc. Polythérapies
WO2016054491A1 (fr) 2014-10-03 2016-04-07 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
AU2014277740B1 (en) * 2014-12-17 2016-02-25 Institute of Organic Chemistry and Biochemistry, ASCR, v.v.i. Novel substituted 7-deazapurine ribonucleosides for therapeutic uses
CN108349985A (zh) 2015-09-14 2018-07-31 无限药品股份有限公司 异喹啉酮的固体形式、其制备方法、包含其的组合物及其使用方法
EP3170830A1 (fr) * 2015-11-17 2017-05-24 Centre National De La Recherche Scientifique Nouveaux composés de 5-azido-5-deoxy-2 : 3-isopropylidene-d-arabinose ; leur procédé de fabrication et leur utilisation pour la synthèse de ara-n3, kdo-n3 et 4ekdo-n3
WO2017161116A1 (fr) 2016-03-17 2017-09-21 Infinity Pharmaceuticals, Inc. Isotopologues de composés isoquinolinone et quinazolinone et leurs utilisations comme inhibiteurs de la kinase pi3k
WO2017214269A1 (fr) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
EP3474856B1 (fr) 2016-06-24 2022-09-14 Infinity Pharmaceuticals, Inc. Therapies combinées
US11267845B2 (en) 2016-11-18 2022-03-08 Arcus Biosciences, Inc. Inhibitors of CD73-mediated immunosuppression
CN110687232A (zh) * 2018-07-04 2020-01-14 郑州泰丰制药有限公司 用高效液相色谱检测l-氯糖差向异构体的方法
US20220152072A1 (en) * 2019-04-05 2022-05-19 Prelude Therapeutics, Incorporated Selective Inhibitors Of Protein Arginine Methyltransferase 5 (PRMT5)
WO2024134541A1 (fr) * 2022-12-20 2024-06-27 iTeos Belgium SA Composés hétérocycliques utilisés en tant qu'inhibiteurs d'ent et composés destinés à être utilisés dans le traitement de cancers

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI904694A7 (fi) * 1989-01-24 1990-09-24 Gensia Pharma Menetelmä ja yhdisteitä AICA-ribosidin antamiseksi ja veren glukoosin alentamiseksi
IL99124A (en) * 1990-08-10 1998-02-22 Gensia Pharma Substituted imidazole analogs of aica riboside
WO1994006438A1 (fr) * 1992-09-11 1994-03-31 The Regents Of The University Of California Analogues de l'adenosine et procede d'intensification de la liberation de l'adenosine

Similar Documents

Publication Publication Date Title
US5646128A (en) Methods for treating adenosine kinase related conditions
WO1994017803A9 (fr) Inhibiteurs de l'adenosine kinase
EP0682519A1 (fr) Inhibiteurs de l'adenosine kinase
EP0496617B1 (fr) Inhibiteurs de kinase d'adénosine
US6211158B1 (en) Desazapurine-nucleotide derivatives, processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof for nucleic acid sequencing and as antiviral agents
US5506347A (en) Lyxofuranosyl analogues of adenosine
US5721356A (en) Orally active adenosine kinase inhibitors
US5763597A (en) Orally active adenosine kinase inhibitors
AU727177B2 (en) Purine L-nucleosides, analogs and uses thereof
US4963662A (en) Fluorinated nucleosides and method for treating retrovirus infections therewith
Bhat et al. Pyrazolopyrimidine nucleosides. 12. Synthesis and biological activity of certain pyrazolo [3, 4-d] pyrimidine nucleosides related to adenosine
AU665184B2 (en) Adenosine kinase inhibitors
WO2004080466A1 (fr) Analogues de la cytidine et methodes d'utilisation
US5384310A (en) 2'-fluoro-2-haloarabinoadinosines and their pharmaceutical compositions
IE902665A1 (en) Nucleoside derivatives and pharmaceutical compositions¹containing them
US4071680A (en) 5'-Deoxy-5-fluoropyrimidine nucleosides
HU199871B (en) Process for producing deazapurine nucleoside derivatives and antiviral compositions comprising said compounds
US5864033A (en) Adenosine kinase inhibitors
Kini et al. Synthesis and antiviral activity of certain guanosine analogs in the thiazolo [4, 5-d] pyrimidine ring system
JPH06228186A (ja) ２’−デオキシ−（２’ｓ）−アルキルピリミジンヌクレオシド誘導体
Hunter et al. [d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor
IE920190A1 (en) Adenosine kinase inhibitors
CA2596142A1 (fr) Analogues nucleosidiques puriques
HU192472B (en) Process for preparing /e/-5-/2-bromo-vinyl/-uracyl derivatives
NZ505554A (en) 8-substituted alpha or beta L guanosine analogs and derivatives useful for modulating Th1 and Th2 activities in a patient