WO1998018430A2 - Antagonistes des recepteurs p2y - Google Patents

Antagonistes des recepteurs p2y Download PDF

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Publication number
WO1998018430A2
WO1998018430A2 PCT/US1997/019922 US9719922W WO9818430A2 WO 1998018430 A2 WO1998018430 A2 WO 1998018430A2 US 9719922 W US9719922 W US 9719922W WO 9818430 A2 WO9818430 A2 WO 9818430A2
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Prior art keywords
receptor
phosphate
group
compound
deoxy
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WO1998018430A3 (fr
Inventor
José L. BOYER
T. Kendall Harden
Kenneth A. Jacobson
Emidio Camaioni
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University of North Carolina at Chapel Hill
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University of North Carolina at Chapel Hill
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Priority to AU55846/98A priority Critical patent/AU5584698A/en
Priority to EP97952172A priority patent/EP0929218A4/fr
Priority to JP52080798A priority patent/JP2001504097A/ja
Publication of WO1998018430A2 publication Critical patent/WO1998018430A2/fr
Publication of WO1998018430A3 publication Critical patent/WO1998018430A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • This invention relates to compounds that are antagonists of P2Y purinergic receptors, and more specifically to antagonists that have competitive antagonist activity at P2Y purinergic receptors.
  • G. Burastock Prog. Biochem. Pharmacol. 16, 141-154 (1980);
  • G. R. Dubyak, G. R., and C. El-Moatassim Am. J. Physiol. 265, C577- C606 (1993); T. K. Harden, et al., Ann. Rev. Pharmacol. Toxicol. 35, 541-579 (1995).
  • Adenine nucleotides activate both ligand-gated ion channels of the P2X superfamily and G-protein coupled receptors of the P2Y superfamily. M.P. Abbracchio et al., Pharmacol. Therap. 64, 445-475 (1994).
  • uridine nucleotides act as agonists at certain subtypes of P2Y receptors. S.E. O'Connor et al., Trends. Pharmacol. Sci. 12, 137-141 (1991); J.M.
  • the present invention is based on the initial discovery of 2 ' - and 3 ' -phosphate derivatives of ATP and UTP that were found to be partial agonists (and consequently, competitive antagonists) of P2Y receptors.
  • adenosine 3',5'- and 2',5'- bz ' sphosphates were found to act as competitive antagonists at the P2Y, receptor. It has now been discovered that a subset of this group of analogs has potent, competitive antagonistic activity without any partial agonist activity at the human P2Y, receptor.
  • these compounds can be described as 2'- and 3'-deoxyadenosine bisphosphate and 2'- and 3'-deoxyuridine bisphosphate analogs containing various structural modifications at, for example, the 2-, 6-, and 8-positions of the adenine rings, on the ribose moiety, and on the phosphate groups.
  • the compounds of the present invention exhibit higher apparent affinities of interaction with the P2Y, receptor than does ATP, and exhibit absolute selectivity for binding to the P2Y, receptor over four other G-protein-linked P 2 receptor subtypes.
  • a first aspect of the invention is a novel compound of Formula I:
  • R is selected from the group consisting of H, lower alkyl, halo, alkoxy, and alkylthio, with H being preferred;
  • R 2 is selected from the group consisting of hydroxy, halo, alkylthio, lower alkyl, substituted lower alkyl, and -NR'R", wherein R' and R" are each independently selected from the group consisting of H, lower alkyl, aroyl, alkoxy, substituted lower alkyl, alkoxy, and alkoxyalkyl; R 3 is selected from the group consisting of H, halo, and lower alkyl, with
  • R 4 is selected from the group consisting of H and lower alkyl, with H preferred;
  • X is selected from the group consisting of O, S, N, and CH 2 ; with O being preferred; and
  • X 2 , X 3 and X 4 are each independently selected from the group consisting of H, hydroxy, amino, lower alkyl, halo, alkoxy, phosphate, thiophosphate, carboxylate, and nitro, or X 2 and X 3 together are cyclophosphate, with phosphate being preferred; together with the pharmaceutically acceptable salts thereof.
  • a second aspect of the invention is a novel compound of Formula II:
  • R is selected from the group consisting of H, lower alkyl, and halo
  • R 2 is selected from the group consisting of H, and lower alkyl; with H being preferred;
  • X is selected from the group consisting of O, S, N, and CH 2 ; with O being preferred; and X 2 , X 3 and X 4 are each independently selected from the group consisting of H, hydroxy, amino, lower alkyl, halo, alkoxy, phosphate, thiophosphate, carboxylate, and nitro, or X 2 and X 3 together are cyclophosphate, with phosphate being preferred; together with the pharmaceutically acceptable salts thereof.
  • a third aspect of the present invention is a method of detecting a P2Y receptor in a biological sample suspected of containing a P2Y receptor, comprising contacting said biological sample with a compound of the present invention that binds selectively to a P2Y receptor, and then detecting the presence or absence of binding of the P2Y receptor-binding compound to a receptor in the biological sample, the presence of binding indicating the presence of a P2Y receptor.
  • Additional aspects of the present invention include methods of treating disorders that respond to treatment with compounds that interfere with the signaling proteins that interact with extracellular adenine or uridine (including ATP-induced vasoconstriction, bladder disease, prostate disease, hyperthyroidism, hyperinsulinemia, and disorders characterized by excessive production of adeno-cortical hormones), the methods comprising administering to a subject in need of such treatment a compound of the present invention as provided above, in an amount sufficient to treat the disorder.
  • compounds that interfere with the signaling proteins that interact with extracellular adenine or uridine including ATP-induced vasoconstriction, bladder disease, prostate disease, hyperthyroidism, hyperinsulinemia, and disorders characterized by excessive production of adeno-cortical hormones
  • a final aspect of the present invention is a pharmaceutical composition useful in the treatment of a disorder characterized by being responsive to treatment with compounds that interfere with the signaling proteins that are utilized by extracellular adenine or uridine nucleotides, the pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of the present invention or a pharmaceutically acceptable salt thereof, in an amount effective to combat the disorder.
  • FIG 1. is a graphical illustration of the effect of sulfate-substituted adenine nucleotide analogs on inositol lipid hydrolysis by turkey erythrocyte membranes.
  • FIG. 2 is a graphical illustration of the effect of adenosine 3' -phosphate, 5'- phosphosulphate on P2Y receptor-mediated activation of phospholipase C in turkey erythrocytes.
  • [ 3 H]Inositol labeled turkey erythrocyte membranes were incubated with the indicated concentrations of adenosine 3 ' -phosphate, 5 ' -phosphosulphate in the absence (filled circles), or in the presence of 1 (open circles), 3 (filled diamonds), 10 (open diamonds), 30 (filled triangles), 100 (open triangles), 300 (filled squares), and 1000 (open squares) nM 2MeSATP.
  • FIG. 3 illustrates competitive inhibition of 2MeSATP-mediated activation of P2 Y receptors by adenosine 3 ' -phosphate, 5 ' -phosphosulphate and adenosine 3 ' ,5 ' bis phosphate.
  • [ 3 H]Inositol labeled turkey erythrocyte membranes were incubated with the indicated concentrations of 2MeSATP in the absence (filled circles), or in the presence of 0.1 (open circles), 0.3 (filled triangles), 1 (open triangles), 3 (filled squares), 10 (open squares), 30 (filled circles), 100 (open circles), 300 (filled diamonds), and 1000 (open diamonds) ⁇ M adenosine 3 '-phosphate, 5 '-phosphosulphate (Panel A) or adenosine
  • FIG. 4 illustrates the effect of or adenosine 3',5'-b/sphosphate on the activation of phospholipase C by ⁇ -adrenergic receptors in turkey erythrocyte membranes.
  • the capacity of the indicated concentrations of or adenosine 3',5'- ⁇ z.sphosphate to stimulate the accumulation of inositol phosphates in the absence (open diamonds) or in the presence (closed diamonds) of 10 ⁇ M isoproterenol was determined as described below in Example 8.
  • adenosine 3',5'-bisphosphate is a competitive antagonist without agonistic activity at the human P2Y, receptor stably expressed in 1321N1 human astrocytoma cells.
  • Panel A cells were incubated with the indicated concentrations of adenosine 3',5'-bz ' .sphosphate in the absence (filled circles) or in the presence of 10 (filled diamonds), 30 (filled triangles), 100 (open triangles), 300 (filled squares), and 1000 nM 2MeSATP (open squares).
  • Panel B the concentration- dependence of 2MeSATP for the activation of phospholipase C in 1321N1 cells was determined in the absence (filled circles), or in the presence of 0.3 (open diamonds), 1 (filled triangles), 3 (open triangles), 10 (filled squares), 30 (open squares), 100 (filled diamonds), and 300 ⁇ M (open circles) adenosine 3',5'-6z ' ,sphosphate.
  • Panel C illustrates
  • FIG. 6 illustrates the lack of agonist or antagonist effects of adenosine 3',5'- bz ' sphosphate on the adenylyl cyclase-coupled P2Y receptor of C6 cells.
  • FIG. 7 illustrates the effects of deoxyadenosine bisphosphate derivatives on phospholipase C in turkey erythrocyte membranes. Both concentration-dependent stimulation of inositol phosphate formation and its inhibition by compounds 2'- Deoxyadenosine-3 ' ,5 ' -bz ' ,sphosphate (compound 4)(triangles) and 3 ' -Deoxyadenosine-
  • FIG. 8 illustrates the effects of N 6 -alkyl analogues of adenosine and 2'- deoxyadenosine ⁇ z ' ⁇ phosphate derivatives on agonist-stimulated phospholipase C in turkey erythrocyte membranes.
  • Membranes from [ 3 H]inositol-labelled erythrocytes were incubated for 5 min at 30°C in the presence of 10 nM 2-MeSATP and the indicated concentrations of the compounds 2'-Deoxy-N 6 -methyladenosine 3 ',5 '-bisphosphate (Compound 9, squares), 2 '-Deoxy-N 6 -ethyladenosine-3', 5' -bisphosphate (Compound 10, triangles), 2'-Deoxy-N 6 -propyladenosine-3 ',5 '-bisphosphate (Compound 11, diamonds), 2'-Deoxy-N 6 -dimethyladenosine-3 ',5 '-bisphosphate (Compound 13, asterisks), and 2 '-Deoxy-N ⁇ -aminohexyladenosine-S', 5 '-bisphosphate (Compound 23, circles).
  • FIG. 9 is a graphical illustration showing the log dose response curves of the P2Y, agonist 2MeSATP in the presence of a control (circles), or 0.1 ⁇ M (diamonds), 0.3 ⁇ M (triangles), l ⁇ M (squares), 3 ⁇ M (asterisks), lO ⁇ M (crosses) and 30 ⁇ M (X-es) of the compound 2 ' -Deoxy-N 6 -methyladenosine 3 ' ,5 ' -bisphosphate (Compound 9).
  • the parallel shifting of the agonist log dose response curve to the right illustrates the competitive antagonist activity of Compound 9. Data is shown in terms of [ 3 H] Inositol Phosphates (percenage of maximum) as a function of the log Molar concentration of 2MeSATP.
  • FIG. 10 is a Schild regression of the data presented in FIG. 9.
  • FIG. 10 the calculation of the ratio of the agonist (2MeSATP) concentration that elicits equal responses in the absence and presence of antagonist (Compound 9) at increasing concentrations (termed the dose ratio) is plotted according to the relationship log(dose ratio-1) vs. log concentration (in Molar) of Compound 9.
  • the compound 9 is indicated to be a competitive antagonist of the P2Y, receptor.
  • FIG. 11 is a graphical illustration the selective binding and specificity of Compound 9 to the P2Y, receptor.
  • Inositol phosphate accumulation in 1321N1 human astrocytoma cells expressing the cloned, human P2Y, (far left), P2Y 2 (second from left) , P2Y 4 (second from right) or P2Y 6 (far right) receptor was measured in the absence (open bars) or presence (filled bars) of Compound 9 disclosed herein.
  • Purinergic receptors are referred to herein according to the guidelines of the IUPHAR Nomenclature Committee, which has provided general recommendations that
  • P2Y receptors G protein-coupled nucleotide receptors
  • that receptors in a subfamily be denoted by numbers that reflect the chronological order in which the sequences of functional receptors have become available to the public domain.
  • the receptor cloned by Chang et al. J Biol. Chem. 270, 26152-26158 (1995)
  • This receptor is referred to herein as the P2Y 6 receptor.
  • the P2Y 2 receptor has been previously referred to in the literature as the P2U purinergic receptor.
  • the term "lower alkyl” is to be broadly interpreted and includes, but is not limited to, Cl to C4 linear, branched, saturated, unsaturated, cyclic, and acyclic alkyls.
  • Halogenated alkyls (e.g., fluoroalkyls, chloroalkyls) are also encompassed by this definition.
  • alkoxy is defined herein to be a residue represented by the formula -OR, with R representing, for example, lower alkyl as defined above. Halogenated alkoxy groups, such as fluoroalkoxides, are also included within this definition.
  • amino refers to the group NR'R", wherein R' and R" are independently selected from H or lower alkyl as defined above, i.e., -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , etc.
  • alkylthio refers to a residue of the formula -SR, where R represents, for example, lower alkyl as defined above.
  • halo refers to a residue selected from the group consisting of -FI, -
  • the term "agonist” is used to refer to a compound that binds to a physiological receptor and mimics the effects of the endogenous regulatory compound.
  • Compounds that bind to physiological receptors and also inhibit or interfere with the binding of the endogenous agonist are generally referred to herein as "antagonists.” If the inhibition caused by the antagonist can be overcome by increasing the concentration of the agonist, ultimately achieving the same maximal effect, then the antagonist is referred to herein as a "competitive antagonist.”
  • the present invention relates to novel compounds, and to methods of using both novel compounds and compounds that are known.
  • Compounds that are illustrative of the compounds of the present invention include those compounds according to Formula I and Formula II, and the pharmaceutically acceptable salts thereof, as provided above in the Summary of the Invention.
  • novel compounds of the present invention are those which are defined according to Formula I above, with the proviso that when R,, R 3 , and R 4 are each H, and m, n, and p are each 1, and q is 1, 2, or 3, and X, is O, and X 4 is phosphate, and X 2 and X 3 are each either hydroxy, H or phosphate or together are cyclophosphate, R 2 is not -NH 2 .
  • Novel compounds of the present invention also include compounds of Formula II as set forth above, with the proviso that when R, and R 2 are H, and p, m, and n are each 1, and q is 1, 2 or 3, and X, is O, X 2 and X 3 are not H, X 2 and X 3 are not -OH, and X 2 and X 3 together are not cyclophosphate.
  • Preferred compounds of the invention are those compounds of Formula I and
  • Formula II that are deoxy at the 2' and 3" positions (R 2 and R 3 in Formulae I and II) of the compound.
  • Other preferred compounds of the present invention are the substituted N 6 analogue compounds of Formula I, wherein (in reference to Formula I), R 2 is -R'R' ',
  • R' is H and R' ' is lower alkyl.
  • Active compounds of the present invention also include the adenosine and uridine 2'- and 3'- sulphonate derivatives of the compounds of Formula I and Formula II provided above, and the adenosine and uridine 2'- and 3'- borate derivatives of the compounds of Formula I provided above.
  • the appropriate starting nucleosides may first purchased or synthesized, and then either phosphorylated or thiophosphorylated.
  • Several intermediates such as 2'-deoxy-2-methylthioadenosine, 8- bromo-2'-deoxyadenosine, N 6 -ethyl and N 6 -propyl 2'-deoxyadenosines, and 3'-deoxy- N 6 -methyladenosine, may be prepared by the skilled artisan by adapting published procedures. See, e.g., L.F. Christensen et al., J. Med. Chem. 15, 735-739 (1972); M.
  • the reaction will typically completed after one hour and may quenched by the addition of buffer (e.g., triethylammonium bicarbonate).
  • buffer e.g., triethylammonium bicarbonate
  • the resulting mixture may be lyophilized, according to the wishes and general knowledge of the skilled artisan.
  • Purification of the compounds of the present invention may be performed using, for example, a Sephadex ion-exchange column with a linear gradient of water/ammonium bicarbonate (0.01 to 0.5 M).
  • the chemical structures of the phosphorylated nucleosides of the present invention may be verified using ⁇ -NMR and 3I P-NMR techniques, as well as high resolution mass spectroscopy, which techniques are known to those skilled in the art. Using ⁇ -NMR it is possible to monitor the chemical shift of ribose protons at 5'- and 2'- (or 3'-) position, and to distinguish them before and after phosphorylation.
  • the active compounds of the present invention may be prepared, utilized, and/or administered by themselves or in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium or potassium salts, alkaline earth metal salt, or ammonium or tetraalkyl ammonium salts represented by the formula NX 4 + (wherein X is a C alkyl group).
  • Pharmaceutically acceptable salts are defined herein as those salts that retain the desired biological activity of the parent compound but do not impart undesired toxicological effects.
  • a method of the present invention is a method of detecting the presence of absence of a P2Y receptor in a biological sample suspected of containing a P2Y receptor. Such methods comprise contacting a biological sample suspected of containing the a P2Y receptor to an active compound of the present invention, which active compound is capable of specifically binding to a P2Y receptor, under conditions which permit the binding of a P2Y receptor to an active compound of the present invention; and then detecting the presence or absence of the binding.
  • Biological samples taken from human or animal subjects for use in this method are generally biological fluids such as serum, blood plasma, or ascites fluid.
  • the sample taken from the subject can be a tissue sample (e.g., biopsy tissue; scrapings; etc.).
  • a biological sample may comprise a cell culture containing cells that may or may not express a P2Y receptor. Any suitable assay format known to one skilled in the art can be used to carry out the detection of the binding of the active compound to the P2Y receptor, one example being the turkey erythrocyte/phospholipase
  • Active compounds useful in the method of the present invention include the novel compounds set forth above, but also include known compounds of Formula I and Formula II above, such as adenosine 3',5'- bz ' sphosphate and adenosine 2',5'-&z ' ,yphosphate. These compounds, although known, have heretofore not been recognized as being able to specifically bind to, for example, the human P2Y, receptor.
  • active compounds according to Formula I and as disclosed herein are particularly useful in detecting the absence or presence of the P2Y, receptor in a biological sample, as specific binding to the P2Y, receptor by these compounds is illustrated below in the Examples section. Additionally, active compounds according to Formula II and as disclosed herein are particularly useful in detecting the presence or absence of P2Y receptors known to be activated by extracellular uridine nucleotides, e.g., the P2Y 2 receptor and the P2Y 4 receptor. Active compounds of the present invention may additionally be used as therapeutic agents that interfere with the signaling proteins used by extracellular adenine and uridine nucleotides.
  • compounds of the present invention are useful in methods of treating disorders characterized as being responsive to treatment with compounds that interfere with the interaction between extracellular adenine and uridine nucleotides and signaling proteins utilized by these nucleotides.
  • disorders include, but are not limited to, ATP-induced vasoconstriction, hyperthyroidism, hyperinsulinemia, and disorders associated with excessive production of adeno-cortical hormones.
  • P2Y receptors have been shown to be highly expressed in bladder and prostate muscle
  • the present invention is also useful in the treatment of disorders of the bladder (e.g., incontinence) and prostate (e.g., prostatic inflammation, prostatic hyperplasia).
  • an active compound as described herein is administered to a subject suffering from a disorder that it characterized as being responsive to treatment with compounds that interfere with the interaction between extracellular adenine and uridine nucleotides and the signaling proteins utilized by these nucleotides, in a therapeutically effective amount.
  • a therapeutically effective amount is defined herein as an amount of the active compound sufficient to inhibit binding between a P2Y receptor and an extracellular adenine nucleotide or extracellular uridine nucleotide.
  • the present invention is concerned primarily with the treatment of human subjects. However, the present invention may also be employed for the treatment of other mammalian subjects, such as dogs and cats, for veterinary purposes.
  • the dosage of a compound of the present invention, or the pharmaceutically acceptable salt thereof will vary depending on the condition being treated and the state of the subject, but generally may be an amount sufficient to achieve dissolved concentrations of active compound in the blood of the subject or at the receptor site of from about 10 "9 to about 10 "4 moles/liter.
  • the daily dose may be divided among one or several unit dose administrations.
  • the dose of active agent will vary according to the condition being treated and the dose at which adverse pharmacological effects occur. One skilled in the art will take such factors into account when determining dosage.
  • compositions of the present invention include those suitable for parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), oral, inhalation, topical (including buccal, sublingual, dermal and intraocular) and transdermal administration.
  • parenteral including subcutaneous, intradermal, intramuscular, intravenous and intraarticular
  • oral inhalation
  • topical including buccal, sublingual, dermal and intraocular
  • transdermal administration may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art.
  • the most suitable route of administration in any given case may depend upon the nature and severity of the condition being treated, and the particular active compound which is being used.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art.
  • active agents or the physiologically acceptable salts thereof are typically admixed with, inter alia, an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet.
  • One or more active compounds may be incorporated in the formulations of the invention (e.g., the formulation may contain one or more additional anti-tubercular agents as noted above), which formulations may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory therapeutic ingredients.
  • Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the formulations may be presented in unit ⁇ dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for- injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free- flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations for oral administration may optionally include enteric coatings known in the art to prevent degradation of the formulation in the stomach and provide release of the drug in the small intestine.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3, 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
  • iontophoresis see, e.g., Pharmaceutical Research 3, 318 (1986)
  • ATP means adenosine 5'-triphosphate
  • PPADS means pyridoxal phosphate 6-azophenyl 2', 4'-disulphonic acid
  • MeATP means adenosine-5'methylenetriphosphate, ( , ⁇ ) or ( ⁇ , ⁇ ) isomers
  • 2MeSATP means 2- methylthioadenosine 5 '-triphosphate
  • DEAE means diethylaminoethyl
  • DMSO means dimethylsulfoxide
  • FAB means fast atom bombardment (mass spectroscopy)
  • HPLC means high pressure liquid chromatography
  • HRMS means high resolution mass spectroscopy
  • PAPS means adenosine-3'-phosphate-5' phosphosulfate
  • TBAP means tefrabutylammonium phosphate
  • TEAA means triethylammonium acetate
  • TEAB means triethylammonium bicarbonate
  • TLC
  • adenosine 3'-phosphate, 5 '-phosphosulphate, adenosine 3',5'-bz,sphosphate, adenosine 2',5'-bz ' sphosphate, and (-) isoproterenol (+)- bitartrate, nucleosides, nucleotides, 23 - 26, ( ⁇ z phosphate analogues), and reagents used for the syntheses described below were obtained from Sigma Chemical Company (St. Louis, MO). 2MeSATP was obtained from Research Biochemicals Inc. (Natick, MA). 2-[ 3 H]myo-inositol (20 Ci/mmol) was obtained from American Radiolabeled
  • Inositol-free DMEM was obtained from Gibco BRL (Grand Island, NY).
  • System A linear gradient solvent system: 0.1 M TEAA/CH 3 CN from 95/5 to 40/60 in 20 min; flow rate 1 mL/min.
  • System B linear gradient solvent system: 5 mM TBAP/CH 3 CN from 80:20 to 40/60 in 20 min; flow rate 1 mL/min.
  • C6 rat glioma cells were grown in Dulbecco's Modified Eagle's Medium
  • DMEM fetal calf serum
  • a humidified atmosphere 95 % > air and 5%> CO 2 .
  • Cells were passaged by trypsinization. Experiments were carried out with confluent cell cultures 2-4 days after plating in 12-well clusters as previously described in J. L. Boyer et al., Br. J. Pharmacol. 116, 2611-2616 (1995). 1321N1 human astrocytoma cells stably expressing the human or turkey P2Y, receptor, or the human
  • P2Y 2 receptor P 2U -purinergic receptor
  • human P2Y 4 -receptor or the human or rat P2Y 6 -receptor
  • DMEM fetal calf serum
  • Example 2 Materials and Methods Turkey Erythrocyte Labeling Fresh blood was obtained from female turkeys by venous puncture and collected into a heparinized syringe. Erythrocytes were washed twice by centrifugation and resuspension with sterile DMEM, followed by a final wash in inositol-free DMEM. One mL of washed packed erythrocytes was resuspended in a final volume of 4.2 mL of inositol-free DMEM in the presence of 0.5 mCi [ 3 H]inositol.
  • This receptor has been extensively studied in turkey erythrocyte membranes, and this system has been applied to identify molecules that have antagonistic (B.Fischer et al., J. Med. Chem. 1993, 36, 3937-3946; J.L. Boyer, Br. J. Pharmacol. 1996, 118, 1959-1964) or competitive antagonistic (J.L. Boyer et al., Br.
  • 2-MeSATP has a high potency for stimulation of inositol phosphate accumulation in membranes isolated from [ 3 H]inositol- labelled turkey erythrocytes.
  • Erythrocyte ghost membranes were prepared from [ 3 H]inositol-labeled cells by hypotonic lysis in 15 volumes of a buffer containing 5 mM sodium phosphate, pH 7.4, 5 mM MgCl 2 , and 1 mM EGTA (lysis buffer). The membranes were washed three times by centrifugation and resuspension with lysis buffer. The final resuspension was in 20 mM Hepes, pH 7.0, to a concentration of 6 mg protein/mL. This preparation was used immediately for assay of phospholipase C.
  • Agonist potencies were calculated using a four parameter logistic equation and the GraphPad software package (GraphPad, San Diego, CA). All concentration effect curves were repeated in at least three separate experiments using duplicate or triplicate assays.
  • adenosine 3 '-phosphate, 5 '-phosphosulphate at the turkey erythrocyte P2Y receptor was examined in order to determine whether sulfate- containing analogues of adenine nucleotides might be potent P2Y receptor agonists that are more resistant to hydrolysis by ectonucleotidases. Relatively small effects of adenosine 3 ' -phosphate, 5 ' -phosphosulphate on inositol phosphate formation occurred
  • FIG. 1 Although detailed analyses illustrated that this stimulation was both concentration-dependent and apparently saturable with an EC 50 of 0.83 + 0.08 ⁇ M (FIG. 1 and Table 2).
  • the maximal effect of adenosine 3 '-phosphate, 5 '-phosphosulphate relative to that of 2MeSATP, ATP, and ADP was somewhat variable, but typically ranged from 10% to 25% of the maximal full agonist effect (Table 2).
  • Each value represents the mean ⁇ SEM of at least four experiments carried out with different membrane preparations.
  • adenosine 3'-phosphate, 5 '-phosphosulphate The capacity of adenosine 3'-phosphate, 5 '-phosphosulphate to augment or inhibit the effects of a submaximal concentration of 2MeSATP was also determined, adenosine 3 '-phosphate, 5 '-phosphosulphate antagonized the stimulatory effect of 10 nM 2MeSATP (FIG. 2) over the same concentration range necessary to observe the stimulatory effects of adenosine 3 '-phosphate, 5 '-phosphosulphate alone.
  • adenosine 3'-phosphate, 5'- phosphosulphate was examined over a broad range of concentrations (1-1000 nM) of 2MeSATP (FIG. 2).
  • adenosine 3'-phosphate, 5'- phosphosulphate produced a concentration-dependent antagonism of the effects of 2MeSATP at all concentrations of 2MeSATP above 3 nM (FIG. 2).
  • adenosine 3'-phosphate, 5 '-phosphosulphate caused a concentration dependent parallel rightward shift of the concentration effect curve of 2MeS ATP (FIG. 3 A).
  • Schild analysis confirmed that the antagonism was apparently competitive, and the pK B of adenosine 3 '-phosphate, 5 '-phosphosulphate was 6.46 + 0.17.
  • This apparent potency of adenosine 3'-phosphate, 5 '-phosphosulphate is 10-fold greater than that of ATP (4.23 + 1.52 ⁇ M) for stimulation of inositol lipid hydrolysis in the same membranes.
  • adenosine 3',5'-bisphosphate also appears to interact with the P2Y receptor with a potency that is greater than or equal to that of the parent ATP molecule. Effects identical to those of adenosine 3 ',5 '-bisphosphate were observed with the isomer adenosine 2 ',5 '-bisphosphate (Table 2).
  • Partial agonist activity also was observed with other adenosine 3'- and 2'- phosphate analogues such as adenosine 2 '-phosphate 5 '-phosphosulfate, and adenosine 2'-phosphate 5'-phosphoribose (data not shown).
  • Adenosine 5 '-phosphosulfate (FIG. 1) and adenosine 5 '-diphosphoribose were full agonists (data not shown) indicating that substitution with phosphate in the 2'- or 3 '- positions of adenine nucleotides is required for antagonistic activity.
  • Other 2' or 3' substitutions did not confer antagonistic properties to adenine nucleotides. For example, 3 '-amino ATP and 3'-benzoylbenzoyl
  • P2Y Receptor Effects on ⁇ -adrenergic receptor The selectivity of the effects of adenosine 3 '-phosphate, 5 '-phosphosulphate and adenosine 3 ',5 '-bisphosphate was confirmed by examining their effects at the phospholipase C-coupled ⁇ -adrenergic receptor natively expressed in turkey erythrocytes.
  • P 2 receptors No effect of either compound as agonists or antagonists was observed at the P2Y receptor of C6 rat glioma cells (FIG. 6). It has been previously shown that this adenylyl cyclase-linked P 2 receptor differs from the phospholipase C-coupled P2Y, receptor in specificity of second messenger signaling and pharmacological selectivity (J. L. Boyer, et al., Br. J. Pharmacol. 116, 2611-2616 (1995)).
  • adenosine 3'-phosphate, 5'- phosphosulphate and adenosine 3 ',5 '-bisphosphate also were neither antagonists nor agonists at the human P2Y 2 (Table 3), the human P2Y 4 (data not shown), or the rat
  • P2Y 6 (data not shown) receptors stably expressed in 1321N1 cells.
  • Nucleoside (0. 1 mmol) and Proton Sponge ® (107 mg, 0.5 mmol) were dried for several hours in high vacuum at room temperature and then suspended in 2 mL of trimethyl phosphate. Phosphorous oxychloride (37 ⁇ L, 0.4 mmol) was added, and the mixture was stirred for 1 h at 0°C.
  • the reaction was quenched by adding 2 mL of triethylammonium bicarbonate buffer and 3 mL of water. The mixture was subsequently frozen and lyophilized.
  • N 6 -Benzoyl-2'-deoxyadenosine-3',5 , -bis(diammonium phosphate) (Compound 12) Starting from 25 mg (0.070 mmol) of N 6 -benzoyl-2'-deoxyadenosine and following the general procedure, 22 mg (0.038 mmol, 54% yield) of the desired compound 12 was obtained.
  • 'H-NMR (D 2 0) d 2.85, (2H, m, CH 2 -2'); 3.96, (2H., bs, CH 2 -5'); 4.43, (IH, bs, H4');
  • TBAP/CH 3 CN from 80/20 to 40/60.
  • the deoxyadenosine nucleoside analogues prepared according to Example 11 above were tested for agonist and antagonist activity in the Phospholipase C (PLC) assay at the P2Y, receptor in turkey erythrocyte membranes. Concentration-response curves were obtained for each compound alone, and in combination with a given concentration of 2-MeSATP (10 nM). In the case of all the compounds tested, essentially no basal inositol phosphate activity was observed, and a very small stimulation occurred in the presence of 1 ⁇ M GTP ⁇ S (data not shown). Addition of 1 OnM 2-MeS ATP resulted in a marked and concentration-dependent activation of the turkey erythrocyte phospholipase C.
  • PLC Phospholipase C
  • Double alkylation of the N 6 amino group in compound 13 resulted in a > 300- fold loss of potency as an antagonist vs 9, and no agonist activity was observed.
  • 6- Chloro and 6-hydroxy analogues, 14 and 15, respectively, were essentially inactive at P2Y, receptors.
  • the 6-methylthio-analogue, 16 was only a very weak antagonist at P2Y, receptors.
  • the presence of a 2'- methoxy group on the ribose moiety, 20, decreased potency by 2.2-fold vs 4, although a restoration of the agonist effect to a very substantial fraction (33% of maximal) was achieved.
  • Replacement of both phosphate groups with thiophosphate, 21, diminished potency as a P2Y, receptor antagonist by 15-fold.
  • the etheno derivative 22 was inactive at the P2Y, receptor.
  • the compound 2'-Deoxy-N 6 -methyladenosine-3',5'-bz,sphosphate (compound 9) was determined to be a potent and competitive antagonist of the P2Y, receptor.
  • log dose response curves of the P2Y, agonist 2MeSATP were determined in the presence of a control (circles), or 0.1 ⁇ M (diamonds), 0.3 ⁇ M (triangles), l ⁇ M (squares), 3 ⁇ M (asterisks), lO ⁇ M (crosses) and 30 ⁇ M (X-es) of
  • FIG. 9 The parallel shifting of the agonist log dose response curve to the right illustrates the competitive antagonist activity of Compound 9.
  • Data in FIG. 9 is shown in terms of [ 3 H] Inositol Phosphates (percenage of maximum) as a function of the log Molar concentration of 2MeSATP.
  • FIG. 10 is the Schild regression of the data presented in FIG. 9. The calculation of the ratio of the agonist (2MeSATP) concentration that elicits equal responses in the absence and presence of antagonist (Compound 9) at increasing concentrations (termed the dose ratio) was plotted according to the relationship log(dose ratio-1) vs. log concentration (in Molar) of Compound 9.
  • FIG. 11 iillustrates the selective binding and specificity of Compound 9 to the P2Y, receptor. Inositol phosphate accumulation in 1321N1 human astrocytoma cells expressing the cloned, human P2Y, (far left), P2Y 2. (second from left) , P2Y 4 (second from right) or P2Y 6 (far right) receptor was measured in the absence (open bars) or presence (filled bars) of Compound 9.

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Abstract

L'invention concerne de nouveaux antagonistes des récepteurs P2Y dérivés de l'ATP et de l'UTP. L'invention concerne en particulier des antagonistes des récepteurs P2Y présentant une activité antagoniste de compétition en ce qui concerne les récepteurs P2Y, en particulier des antagonistes des récepteurs P2Y qui se fixent de façon sélective aux récepteurs P2Y1. L'invention concerne également des procédés permettant de détecter des récepteurs P2Y dans un échantillon biologique.
PCT/US1997/019922 1996-10-30 1997-10-23 Antagonistes des recepteurs p2y Ceased WO1998018430A2 (fr)

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US6348587B1 (en) 1998-02-25 2002-02-19 Emory University 2′-Fluoronucleosides
WO2002062816A1 (fr) * 2001-02-07 2002-08-15 Celltech R & D Limited Nucleotides et dinucleotides non naturels
JP2003519080A (ja) * 1998-07-17 2003-06-17 アストラゼネカ アクチボラグ 新規のトリアゾロ［４，５−ｄ］ピリミジン化合物
WO2005113511A1 (fr) * 2004-05-12 2005-12-01 Bristol-Myers Squibb Company Antagonistes uréiques du récepteur p2y1 pour le traitement des syndromes thrombotiques
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