EP0682519A1 - Inhibiteurs de l'adenosine kinase - Google Patents

Inhibiteurs de l'adenosine kinase

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Publication number
EP0682519A1
EP0682519A1 EP94909558A EP94909558A EP0682519A1 EP 0682519 A1 EP0682519 A1 EP 0682519A1 EP 94909558 A EP94909558 A EP 94909558A EP 94909558 A EP94909558 A EP 94909558A EP 0682519 A1 EP0682519 A1 EP 0682519A1
Authority
EP
European Patent Office
Prior art keywords
amino
hydrogen
halogen
alkyl
deoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94909558A
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German (de)
English (en)
Other versions
EP0682519A4 (fr
Inventor
Gary Steven Firestein
Bheemarao Ganapatrao Ugarkar
Leonard Paul Miller
Harry Edward Gruber
David Andrew Bullough
Mark David Erion
Angelo John Castellino
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Sicor Inc
Original Assignee
Sicor Inc
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Publication date
Application filed by Sicor Inc filed Critical Sicor Inc
Publication of EP0682519A1 publication Critical patent/EP0682519A1/fr
Publication of EP0682519A4 publication Critical patent/EP0682519A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

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. Sci.. 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 sa to be a potent vasodilator, and is beiieved 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.
  • Adenosine 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..
  • 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 cell 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 adenos kinase but were reported to have Kj's of greater than 800 nM (Caldwell and
  • 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
  • the AK- cells used in this study were said t release adenosine at an accelerated rate; the concentration of adenosine in the growth medium was reported to be elevated compared to the normal cells (Gree J. Suoramol. Structure. 1980, 13:175-182).
  • adenosine uptake was reportedly inhibited by the adenosine kinase inhibitors, 5 iodotubercidin and 5'-deoxy-5-iodotubercidin (Davis et al., Biochem. Pharmacol.. 1984, 33:347-355).
  • inhibition of uptake and intracellular trapping via phosphorylation does not necessarily result in increased extracellular adenosine since the adenosine could enter other metabolic pathways or the percentage of adenosine being phosphorylated could be insignificant compared to the total adenosine removed.
  • adenosine and certain inhibitors of adenosine catabolism 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., Cytobios. 1987, 50:7-12).
  • the pyrrolo[2,3- d]pyrimidines, 5-iodotubercidin and 5'-deoxy-5-iodotubercidin have been report to cause pronounced general flaccidity and much-reduced spontaneous locomo 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 (Dav 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 availabilit
  • 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 concentration biological systems.
  • In vivo inhibition of adenosine kinase prevents phosphorylation of adenosine resulting in higher local concentrations of endogenous adenosine.
  • this effect is most pronounced in regions producing the most adenosine such as ischemic regions.
  • the beneficial effects of adenosine are enhanced in a site and event specific manne and toxic systemic effects are reduced.
  • the present invention is directed to novel nucleoside analogs which comprise a 5'-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 kina inhibitors may be used clinically to treat medical conditions where an increased localized adenosine concentration is beneficial.
  • the present invent is directed to the prophylactic and affirmative treatment of ischemic conditions s as myocardial infarction, angina, percutaneous transluminal coronary angiogra (PTCA), stroke, other thrombotic and embolic conditions, neurological condition 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 as myocardial infarction, angina, percutaneous transluminal coronary angiogra (PTCA), stroke, other thrombotic and embolic conditions, neurological condition 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.
  • 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 disorder which vascular leakage is involved.
  • the present invention is direct 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 hav 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 aromat 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 substituen such being advantageously lower alkyl, hydroxy, lower alkoxy, lower alkanoylo halogen, cyano, trihalomethyl, lower acylamino or lower alkoxycarbonyl.
  • "Optionally substituted naphthyl” refers to 1- or 2-naphthyl or 1- or 2-naph preferably substituted by lower alkyl, lower alkoxy or halogen.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ri atoms in the aromatic ring and the remainder of the ring atoms carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl, a the like, all optionally substituted.
  • Optionally substituted furanyl represents 2- or 3-furanyi 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- 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 attachmen the phenyl ring, advantageously para; biaryl is also represented as the -C6H4- 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 option substituted.
  • 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 m 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 an 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)-.
  • carboxylate or “carboxamido” refers to -CONR2 wherein eac 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-cha branched chain and cyclic groups.
  • alkenyl refers to unsaturated hydrocarbyl groups which contai least one carbon-carbon double bond and includes straight-chain, branched-ch and cyclic groups.
  • alkynyl refers to unsaturated hydrocarbyl groups which contai 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.
  • hydrocarbylamino refers to -NRR' wherein R is hydrocarbyl an is independently selected hydrocarbyl or hydrogen.
  • mercapto refers to SH or a tautomeric form.
  • 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 reac 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 skille 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 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 endothelial 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 stu
  • 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, mercapt alkylthio, azido, cyano, halogen, or B' is alkenyl or alkynyl;
  • Ci and C2 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 hydrox 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.
  • One preferred group of these 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, 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 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, pyrrolidinyl 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 1 is -(CH2)nB 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, aralkyloxy, alkylthio, arylthio, aralkylthio, optionally substituted indolinyl or indolyl, pyrrolidinyl 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, tnazolyl or triazinyl, E and G are both hydrogen, th F is not amino.
  • adenosine kinase inhibitors which comprise modified purine nucleosides of the formula:
  • A is oxygen, methylene or sulfur;
  • B' 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 C2 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, pyrrolidinyl 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 hydrocarbyiamino, E and G are hydrogen 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, alkylamin acylamino, hydrocarbyloxycarbonylamino, mercapto, alkylthio, azido, or either both of B' or B" is independently alkenyl or alkynyl;
  • Ci and Cv and C-2 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 C2' i carbonyl 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 n
  • E is independently hydrogen, halogen, alkyl, or alkylthio;
  • L is an optionally substituted piperaziny
  • ALKL is a divalent alkylene radical of 2 to 24 carbon atoms
  • G is hydrogen, halogen, alkyl alkylthio.
  • G groups include hydrogen.
  • Preferred Ci and C 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, aralk 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.
  • Preferred compounds include those where B' is -(CH2)nB, and n is 1 or 2, more preferably n is 1.
  • B may preferably include hydrogen, halogen, alkyl, amin 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 Formul contain a 5-modified 1- ⁇ -D-ribofuranosyl group and that isomer comprises a particularly preferred diastereomeric and enantiomeric form for compounds of t present invention. Aptly, 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.
  • compounds having Formula I wherein B' replaced by -CH2OH, as adenosine kinase inhibitors are included in the scope of this invention.
  • 5'-phosphates may be toxic, mutagenic or teratogenic
  • 5'-hydroxy compounds whi can serve as substrates for phosphorylation enzymes may not comprise preferr 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 tho where G is hydrogen and A is oxygen.
  • Preferred D groups include hydrogen, al aryl, aralkyl, cyano, alkoxy, aryloxy, aralkoxy, alkenyl or alkynyl, more preferabl 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, mor 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 preferabl amino or arylamino.
  • Certain preferred compounds of Formula II may include F groups which comprise optionally substituted anilino groups, (ii) Preferred Pyrrolo[2.3-d]pyrimidines 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 aryl, 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 Purines 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, ar or aralkyl, more preferably amino or arylamino. ijy 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 variousl substituted purine nucleosides or pyrrolo[2,3-d]pyrimidine nucleosides, includi novel and improved synthesis of 5'-deoxy-5-iodotubercidin; and pyrazolo[3,4- djpyrimidine 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 azid (2a) prepared from 2',3'-0-isopropylideneinosine, is activated for nucleophilic attack at position six by chlo nation with thionyl chloride/dimethylformamide.
  • Standard reagents may also be used to activate position six of compound (2) su as thionyl bromide, phosphorous oxychloride, triphenyiphosphine dibromide- thiophenol-potassium permanganate or hexamethyldisilazane-ammonium sulf
  • 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 ( ⁇ a).
  • Reductio the azide ( ⁇ a) to the amine (£) is effected by catalytic hydrogenation with a cata such as platinum oxide, palladium on carbon and the like.
  • a cata such as platinum oxide, palladium on carbon and the like.
  • triphenyiphosph is used to selectively reduce the azide moiety to the amine.
  • N- acylamino (7a) and hydrocarbyloxycarbonylamino (7b) compounds the azide ( is reduced to the amine and treated with an acyl anhydride or acyl chloride or a chloroformate and deblocked to give (7a) or (7b) respectively.
  • Analogous processes are used to prepare the 2- and 8- substituted analogs beginning wit appropriately substituted intermediates.
  • An alternative synthesis of 5'-amino an 5'-hydrocarbyiamino compounds comprises deblocking a 2',3 , -isopropyiidene- tosylate with aqueous acid and then reacting the deblocked tosylate with amm or a lower hydrocarbylamine. Further description of these procedures is set fort the Examples.
  • 5'-deoxy purine nucleosides A similar process is used to prepare 5'-deoxy purine nucleosides.
  • the appropriately substituted 5'-deoxy-2',3'-0-isopropylideneinosine (2k) is chlorin or activated using other reagents described above, aminated to (4£) and subsequently deblocked to afford the ⁇ '-deoxy nucleoside ( 5b ) .
  • a key step comprises sodium salt glycosylation method (K. Ramasamy et al., Tetrahedron Letters. 198 28:5107) using the anion of a substituted 4-chloropyrrolo[2,3-d]pyrimidine (1£) 1-chloro-2,3-0-isopropylidene-5-0-tert-butyldimethylsilyl- ⁇ -D-ribofuranoside (1
  • This method is also suitable for direct preparation of ribofuranosides wherein th hydroxy group has been replaced with substituents such as hydrogen or azido extended with additional carbons (Figure 5).
  • the azide sugars further provide f facile synthesis of 5'-amino nucleosides by reductions of the azide function after ribosylation.
  • An alternative to the sodium salt glycosylation method is a solid-liq phase transfer reaction using the same substrates and potassium hydroxide in place of sodium hydride as described by Rosemeyer H., and Seela, F, Helvetic Chimica Acta. 1988, 71 :1573.
  • Preparation of the 5-substituted ribose analogs and homologs is outlined
  • the 5-substituted-5-deoxy ribose analogs (1_Q) are prepared b tosylation of the protected ribose (£), displacement of the tosylate by appropriat nucleophiles and subsequent deblocking (Synder, J.; Serianni, A.; Carbohydrat Res.. 1987, 163:169).
  • the ribose homologs ( Figure 5) are prepared by oxidatio the protected ribose (£) to the aldehyde (11) (Moorman, A.; Borchaedt, R.; Nucl Acid Chemistrv-Part III. Townsend, L; Tipson, R.; John Wiley & Sons, 1986).
  • Th aldehyde is homologated via the appropriate Wittig reagent to give the key intermediate protected vinyl sugar (12).
  • the protected intermediate is deblocke give the vinyl ribose homolog (16a) or reduced to (13) and then deblocked to gi the saturated deoxy analog (16b).
  • the vinylated intermediate (12) hydroborated and oxidized affording the protected homologous ribose (14a) wh 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-isopropyiidine ketals ( Figure 6) which are chlorinated stereoselectiveiy to 5-modified 1-chloro- ⁇ -D-ribofuranosi (17) using carbon tetrachloride and hexamethylphosphorous triamide (Wilcox, Qtaski. R.: Tetrahedron Lett.. 1986, 27:1011 ).
  • ribosyl protected 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine nucleosides an 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 a 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 condensati 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 esteri 5-hydroxy, 5-azido or 5-deoxyribofuranoside in the presence of a Lewis acid su 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, toiuate, 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 2k 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 var substituted 4-amino or 4-hydrocarbylaminopyrazoIo[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 t 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- d]pyhmidine 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 prep 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 triphenyiphosphine must be present as well as a base such as sodium carbon
  • the resulting arylated nucleosides are important examples of the present inve 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 al 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 al 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 chlor 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- djpyhmidines 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 endotheli 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 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., Lan£eil(8529):355 (1987); Damas et al., Crit. Care Med.
  • Example H may indicate a broader therapeutic role for adenosine kinase inhibitors, including the novel compound disclosed herein.
  • Example J describes the efficacy of GP-1-515 in the treatme endotoxic shock in pigs, as the treated animals did not develop the hypoxemia
  • Plasma ieakage An integral part of the inflammatory response involves an increase of vascular permeability to plasma proteins, herein termed “plasma ieakage” or “vascular leakage”.
  • Ieakage occurs when there is a change of the barrier properties of the vasculature in a tissue, and may be due to contraction of activ
  • Example L Additional support for the use of adenosine kinase inhibitors in burn treatment is presented in Example L. Bacterial infection is a common occurren during burn recovery. In a burn model, the use of GP-1-515 was shown to
  • 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, 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 a 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 b for example, inert diluents, such as calcium carbonate, sodium carbonate, lacto calcium phosphate or sodium phosphate; granulating and disintegrating agent 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 tal Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestin tract and thereby provide a sustained action over a longer period. For example time delay material such as glyceryl monostearate or glyceryl distearate alone with a wax may be employed.
  • time delay material such as glyceryl monostearate or glyceryl distearate alone 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 paraf or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraf 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., polyoxyethyle 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-oleate
  • 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 i 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 oleaginou suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginou 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed 5 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 formulatio 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 5 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 5 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 suc as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, 0 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 th 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 an 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 saiicylate.
  • 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 blo 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 (lyophiiized) 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 uni daily sub-dose, or an appropriate fraction thereof, of an adenosine kinase inhibito 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 to 20 nmole/min/kg with, for example, an infusion volume of 30 mUhr. 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 prepare 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 understood further by the examples which illustrate some of the processes by which these compounds are prepared. These examples should not however be construed a 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) inosin 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-r5-deoxy-2.3-Q-(1-methylethylidene)-1 D-ribofuranosyl]purine A solution of the blocked 5'-deoxyinosine (1.4 g, 4.8 mmol), tetraethylammonium chloride (1.9 g, 11.5 mmol), diethylaniiine (1.2 mL, 7.2 mm and phosphorous oxychloride (3.35 mL, 36 mmol) in CH3CN (24 mL) was reflu for 10 minutes then evaporated. The residue was dissolved in CH2CI2, washe 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'- deoxyadenosmes
  • 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, 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 pyridine (40 mL) was added with stirring, p-toluenesulfonyl chloride (6.96 g, 0.3 mol). The solution was sealed and stored at 0-10°C for 72 hours then poured in cold H2O (30 mL). The solid was collected by filtration and rinsed 3x with H2O.
  • p-toluenesulfonyl chloride 6.96 g, 0.3 mol
  • EXAMPLE 33 Preparation of 6-(N-lndolinyl)-9-(5-methylamino-5-deoxy-1 - ⁇ -D- ribofuranosvDpurine 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-d]pyrimidine
  • 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-d]pyrimidine 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. A 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-ribofurano 5-Deoxy-D-ribofuranose (8.g, 60 mmole) was dissolved in DMF (25 mL) to the solution was added dimethoxypropane (10 mL) and p-toluenesulfonic aci (150 mg). The reaction was stirred overnight then neutralized with OH' resin. T mixture was filtered, concentrated and the residue chromatographed on silica g Collected like fractions and evaporated to yield 4.1 g (39% yield) of viscous liqu
  • 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 acid (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 stirhng at room temperature, a saturated solution of ammonium chloride in water (180 mL 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 evaporat 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).
  • the benzoylated sugar (Example 54) was dissolved in a mixture of dry (20 mL), 2,2-dimethoxypropane (20 mL) and p-toluenesulfonic acid (200 mg) stirred at room temperature. After 2 hours the reaction mixture was neutralized strongly basic ion exchange resin and the resin removed by filtration and was The combined washings and filtrate were evaporated and the residue was pur by chromatography. The pure product obtained was a glassy solid.
  • the minor product, Rf 0.7, (10%) was identified as 6-deoxy- methyl-2,3-0-(1-methylethylidene)-D-allofuranoside.
  • This compound may be prepared by t-butyidimethylsilylation 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
  • EXAMPLE 64 Pre p aration of 6-azido-5.6-dideoxy-2.3-0- ( 1-methylethylidene)-D- allofuranose
  • the protected nucleoside was deblocked by dissolving in 90% trifluoroace acid and stirring for 2 hours. The solvent was evaporated and chased with methanol (3x). The product was crystallized from EtOH.
  • EXAMPLE 1 14 Preparation of 5-lodo-7-(5-deoxy-1- ⁇ -D-ribofuranosyl)pyrrolor2.3- dlPyrimidin-4(3H)-thione
  • the solvent was evaporated and the residue was triturated with water (10 mL).
  • the solid was collected by filtration, washed with water and dried in air: Yield 200 mg (81%); m.p. 161-163°C.
  • 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.
  • EXAMPLE 132 Preparation of 4-Amino-3-(cvanomethyl )p yrazolof3.4-d pyrimidine The above-identified compound was prepared as described: Carboni, R.,; Coffman, D.,; Howard, E.; J.Am. Chem. Soc. 1958 80:2838.
  • EXAMPLES 140-144 General Procedure for the Preparation of 5-Amino-3-aryl-4- cyanopyrazoles 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 mUg) 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.
  • the above-identified compounds may be prepared from the correspondin pyrazolo[3,4-d]-pyr ⁇ m ⁇ dones by a procedure analogous to the one described in Example 2.
  • EXAMPLE 171 Preparation of 3-Bromo-1-f2.3-Q-M-methylethylidene)-1- ⁇ -D- ribofuranosyl]pyrazolo[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 HCI (6.5 mL) and dimethoxypropane (20 mL) in 1.1 L of acetone. The mixture was stirred 45 minutes. Na2C03 (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-f2.3-0-(1-methylethylideneV5-0-(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 H2O.
  • 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 NaHC03, H2O and dried .
  • Concentration of the CH2CI2 solution and chromatography of the residue gave the purified isopropyiidene N4- substituted compounds.
  • the isopropyiidene 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-hbofuranoside 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% NaHC ⁇ 3. 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 oc and ⁇ isomers.
  • EXAMPLE 204 General Procedure for the Preparation of 3-Substituted 1-(5-azido- 5-deoxy-2.3-0-diacetyl-1- ⁇ -D-ribo-furanosyl)-4-chloropyrazolo[3.4- dlpyrimidines.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 triphenyiphosphine 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, evaporated, extracted with hot ethanol and the extract then evaporated and 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
  • test compounds 25 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 incubate in the assay mixture for 20 min. at 37 °C. From each reaction mixture, 20 ⁇ l portions were removed and spotted on 2 cm 2 pieces of Whatman DE81 filter pap
  • A1 receptor binding affinity was determined using 0.5 mL mixture containing 50 mM Tris HCI, 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.
  • 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 aipha-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 compounds were incubated in the assay mixture for 10 min at 37 °C. The reaction was monitored continuously for oxidation of NADH from the change in absorbance at 340 nm.
  • the compounds designated GP-1-515, GP-1-608 GP-1-683, GP-1-695, GP-1-718, GP-1-704, GP-1-665, and GP-1-667 were found to have an IC50 of less than 10 nM in the adenosine kinase inhibition assay.
  • 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 10 ⁇ M in the A1 receptor assay and an IC50 greater than 1000 ⁇ M in the adenosine deaminase inhibition assay.
  • adenosine kinase in intact cells 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.
  • Capillary 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 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 I.V. HEMODYNAMICS IN THE RAT
  • 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 Dawiey 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 mUmin 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 in vivo See Figure 1.
  • 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 ]n 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 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- 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- -456. IN A MODEL OF INFLAMMATION
  • 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 contro from day 1 through day 19.
  • Hind paw volume was measured by Mercury displacement. On day 19, total mean hind paw edema, in mL, was 1.41 ⁇ 0.21 for treated rats versus 2.55 ⁇ 0.20 for untreated rats (p ⁇ 0.05).
  • This model demonstrated significant reduction of hind paw edema in adjuvant arthritis in animals treated with the adenosine kinase inhibitor, GP-1-456.
  • 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 covered with a blanket to maintain normal body temperature. A pentobarbital infusion was maintained at 10 mg/kg/hr. The pigs were ventilated with 30% 02 u a Harvard large animal respirator at 7-10 breaths/min in order to achieve a blood of approximately 7.45-7.50.
  • a bolus of 4 mg of Pancuronium bromide was given t inhibit muscle contraction in response to the cautery and the animals were hydrat with a continuous infusion of saline at 60-80 cc/hr.
  • a left thoracotomy was perfor in the third intercostal space and the pulmonary artery, carotid artery, external jug 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 connecte 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.
  • Carrageenan and histamine induced plasma Ieakage 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 plasm Ieakage 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 in the tissue in this model as occurs with carrageenan.
  • Example L EFFECT OF AN ADENOSINE KINASE INHIBITOR IN A BURN MODE
  • Animals also received an i.p. injection of morphine sulfate (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 befo the burn and for 24 hours thereafter. After 48 hours, the animals were sacrificed cervical dislocation and the abdomen was opened using aseptic techniques. Mesenteric lymph nodes were harvested and weighed in sterile bags, homogenized in Trypticate Soy Broth (BBL, Becton Dickinson Microbiology System, Cockeysville, MD).

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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.
EP94909558A 1993-02-03 1994-02-03 Inhibiteurs de l'adenosine kinase. Withdrawn EP0682519A4 (fr)

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IL108523A0 (en) 1994-05-30

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