WO2009006089A2 - Agonistes des récepteurs d'adénosine a2 - Google Patents

Agonistes des récepteurs d'adénosine a2 Download PDF

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Publication number
WO2009006089A2
WO2009006089A2 PCT/US2008/067978 US2008067978W WO2009006089A2 WO 2009006089 A2 WO2009006089 A2 WO 2009006089A2 US 2008067978 W US2008067978 W US 2008067978W WO 2009006089 A2 WO2009006089 A2 WO 2009006089A2
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
group
nmr
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PCT/US2008/067978
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English (en)
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WO2009006089A3 (fr
Inventor
Kenneth A. Jacobson
Zhan-Guo Gao
Hayamitsu Adachi
James M. Downey
Yanping Liu
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Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
South Alabama Medical Science Foundation
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Application filed by Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services, South Alabama Medical Science Foundation filed Critical Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
Publication of WO2009006089A2 publication Critical patent/WO2009006089A2/fr
Publication of WO2009006089A3 publication Critical patent/WO2009006089A3/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
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • a 2A , A 2B , and A 3 adenosine receptors
  • Activation or blocking one or more of these ARs leads to useful therapeutic applications.
  • activation of the A 2 ⁇ AR can induce angiogenesis, reduce vascular permeabilization, increase production of the anti- inflammatory cytokine IL-10, increase chloride secretion in epithelial cells, or increase release of inflammatory mediators from human and canine mast cells.
  • a 2 ⁇ AR agonists for use in therapeutic applications.
  • the invention provides A 2B adenosine receptor (AR) agonists of formula I.
  • exemplary compounds of formula I have enhanced potency at the A 2 ⁇ AR and reduced potency at other AR subtypes, wherein R 1 -R 4 , Z, and n are described below in detail.
  • compositions comprising at least one compound of formula I and methods of use thereof, for example, in a method of treating a disease based on the modulation of the adenosine system, e.g., septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, myocardial ischemia, and reperfusion injury.
  • adenosine system e.g., septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, myocardial ischemia, and reperfusion injury.
  • Figure 1 depicts chemical structures of exemplary compounds of formula I (8 and
  • Figure 2 depicts a reaction scheme to prepare intermediates for the 2-ether component of compounds of formula I in accordance with an embodiment of the invention.
  • Figure 3 depicts another reaction scheme to prepare intermediates for the 2-ether component of compounds of formula I in accordance with an embodiment of the invention.
  • Step (a) (i): TsCl, pyridine, CH 2 Cl 2 ; (ii): 3-butyn-l-ol, Pd(PPh 3 ) 2 Cl 2 , CuI, Et 3 N, DMF, 70 0 C; step (b): I 2 , PPh 3 , imidazole, Et 2 O-MeCN, room temperature; and step (c): LAH, THF, 0 0 C - room temperature.
  • Figure 4 depicts a reaction scheme to prepare compounds 8, 17-36, and 119-127 in accordance with an embodiment of the invention.
  • Figure 5 depicts a reaction scheme to prepare compound 39 in accordance with an embodiment of the invention.
  • step (b) (i): EtNH 2 HCl, DIPEA, DMF, 140 0 C;
  • Figure 6 depicts a reaction scheme to prepare compound 40 in accordance with an embodiment of the invention.
  • FIG. 7A depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 ( ⁇ ) in comparison to 2 ( ⁇ ) at the Ai adenosine receptors.
  • Figure 7B depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 ( ⁇ ) in comparison to 2 ( ⁇ ) at the A 2A adenosine receptors.
  • Figure 7C depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 ( A ) in comparison to 2 ( ⁇ ) at the A 2B adenosine receptors.
  • Figure 7D depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 ( ⁇ ) in comparison to 2 ( ⁇ ) at the A 3 adenosine receptors.
  • Figure 8 depicts the percent of risk zone infracted in an isolated rabbit heart for a control group and a group that had been administered 200 nM of 28 in accordance with an embodiment of the invention.
  • Figure 9 depicts the infarct size (cm ) as a function of risk size (cm ) in accordance with an embodiment of the invention.
  • the symbol • represents the control group, whereas O represents 28.
  • the present invention provides a compound of formula I or pharmaceutically acceptable salt thereof:
  • R 1 is selected from the group consisting of aryl, cycloalkylaryl, heterocycloalkylaryl, heteroaryl, heterocycloalkyl, and arylheterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of C M2 alkyl, hydroxyl, Ci -I2 alkoxy, halo, tosyl (Ts), CN, -C(O)OH, aminocarbonyl, amino, C 1 - J2 dialkylamino, and Ci -J2 alkylamino;
  • Z is a bond or -CH 2 -;
  • n is an integer of 1 to 4.
  • R 2 is selected from the group consisting Of-CH 2 OH, aminocarbonyl, Cj -J2 alkylaminocarbonyl, and di-Cj.j ⁇ alkylaminocarbonyl;
  • R 3 and R 4 are the same or different and each is selected from the group consisting of hydrogen, C J -CJ 2 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 30 aryl, and imidamido;
  • R 2 is -CH 2 OH, and R 3 and R 4 are hydrogen, then -0-(CH 2 ) H -Z-R 1 is not benzyloxy, phenylalkoxy or a substituted phenylalkoxy, thiophenylalkoxy or a substituted thiophenylalkoxy, pyridylalkoxy, indolylalkoxy, naphthylalkoxy, biphenylalkoxy, or indolylalkoxy.
  • R 1 is selected from the group consisting Of C 6-3O aryl, heteroaryl, heterocycloalkyl, C 5-7 cycloalkyl-C 6-3 o aryl, heterocycloalkyl-Ce ⁇ o aryl, C 6-30 aryl- heteroaryl, and C 6-30 aryl-heterocycloalkyl.
  • R 1 is selected from the group consisting of
  • C 6-3O aryl e.g., phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl
  • a heteroaryl consisting of one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom (e.g., pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thiophenyl, isothiazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolo[2,3-c]
  • R 5 and R 5 are the same or different and each is hydrogen or 1 to 3 substituents individually selected from the group consisting of Ci -I2 alkyl, hydroxyl, Ci -I2 alkoxy, halo, tosyl (Ts), CN, -C(O)OH, aminocarbonyl, amino, Ci -I2 dialkylamino, and Ci -I2 alkylamino; and
  • R 6 is selected from the group consisting of hydrogen, Ci -I2 alkyl, C 3-8 cycloalkyl, and C 6-30 aryl.
  • R 1 is selected from the group consisting of
  • R 1 is selected from the group consisting of
  • R 5 and R 5 are the same or different and each can be hydrogen, Ci -I2 alkyl, hydroxyl, C 1-I2 alkoxy, halo, or tosyl.
  • R 1 is selected from the group consisting of
  • n is 1, 2, or 3, particularly n is 2 or 3. In especially preferred compounds, n is 2.
  • R 2 is -CH 2 OH or C M2 alkylaminocarbonyl (e.g., N-methylcarboxaminocarbonyl, N-ethylcarboxaminocarbonyl, N- propylcarboxaminocarbonyl) .
  • C M2 alkylaminocarbonyl e.g., N-methylcarboxaminocarbonyl, N-ethylcarboxaminocarbonyl, N- propylcarboxaminocarbonyl
  • R 3 and R 4 are the same or different and each is selected from the group consisting of hydrogen, Ci-Ci 2 alkyl, and imidamido.
  • alkyl implies a straight or branched alkyl moiety containing from, for example, 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • moieties include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.
  • cycloalkyl means a cyclic moiety containing from, for example, 1-3 rings (i.e., monocyclic, bicyclic, tricyclic, or spiro), 3 to 8 carbon atoms per ring, preferably from 5 to 8 carbon atoms, more preferably from 5 to 6 carbon atoms.
  • moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like.
  • heterocycloalkyl means a cycloalkyl moiety having one or more heteroatoms selected from nitrogen, sulfur, and/or oxygen.
  • a heterocycloalkyl is a 5 or 6-membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur.
  • the heterocycloalkyl can be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Examples of such heterocyclic rings are pyrrolinyl, pyranyl, piperidyl, tetrahydrofuranyl, tetrahydrothiopheneyl, and morpholinyl.
  • arylheterocycloalkyl refers to a heterocycloalkyl, as defined herein, that is substituted with an aryl group, as defined herein, as a fused ring, e.g., benzo. Examples include 2,3-dihydrobenzo[b][l,4]dioxinyl, 2-indolinyl, and 3-indolinyl.
  • cycloalkylaryl and “heterocycloalkylaryl” refer to an aryl, as defined herein, that is substituted with a cycloalkyl group or a heterocycloalkyl group, respectively, as defined herein, or as a fused ring, e.g., benzo.
  • cycloalkylaryl groups include 5-, 6-, 7-, or 8-1,2,3,4-tetrahydronaphthalenyl and 4-, 5-, 6-, or 7-2,3-dihydro-lH-indenyl.
  • heterocycloalkylaryl examples include 5-, 6-, 7-, or 8-1,2,3,4-tetrahydroquinolinyl, 5-, 6-, 7-, or 8-1,2,3,4-tetrahydroquinoxalinyl, and 5-, 6-, 7-, or 8-2,3-dihydrobenzo[b][l,4]dioxinyl.
  • heteroaryl refers to aromatic 4, 5, or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic aryl groups having one or more heteroatoms (O, S, or N).
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized.
  • the heteroaryl group can be attached at any available nitrogen or carbon atom of any ring.
  • Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,
  • arylheteroaryl refers to heteroaryl, as defined herein, that is substituted with an aryl group, as defined herein, as a fused ring, e.g., benzo.
  • arylheteroaryl groups include benzimidazolyl, indolyl, indazolyl, benzo-l,2,3-triazolyl, 2-benzo[d] oxazolyl,
  • alkoxy embraces linear or branched alkyl groups that are attached to a an ether oxygen.
  • the alkyl group is the same as described herein. Examples of such substituents include methoxy, ethoxy, t-butoxy, and the like.
  • alkylamino refers to a group with one hydrogen and one alkyl group directly attached to a trivalent nitrogen atom.
  • dialkylamino refers to a group with two of the same or different alkyl groups directly attached to a trivalent nitrogen atom.
  • aminocarbonyl refers to the group -C(O)NH 2 .
  • alkylaminocarbonyl and “dialkylaminocarbonly” refer to the group -C(O)NRR', in which
  • R is hydrogen or an alkyl group and R' is the same or different alkyl group as described herein.
  • imidamido also known as guanidino, refers to the group
  • halo as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.
  • fused includes a polycyclic compound in which one ring contains one or more atoms preferably one, two, or three atoms in common with one or more other rings.
  • Ci -8 , Ci -6 , or CM alkyl, alkylamino, etc. any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1-8 carbon atoms e.g., Cj-Cg
  • 1-6 carbon atoms e.g., C I -C O
  • 1-4 carbon atoms e.g., Ci-C 4
  • 1-3 carbon atoms e.g., C1-C3
  • 2-8 carbon atoms e.g., C 2 -C 8
  • any chemical group e.g., alkyl, alkylamino, etc.
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon
  • the compounds of formula I can be prepared by any suitable method.
  • 2', 3', 5'-triacetyl-6-chloroguanosine can be synthetically modified to prepare 2- ether-substituted 2', 3', 5'-triacetyl-6-chloroadenosine derivatives.
  • a suitable amine e.g., ammonia, ethylamine hydrochloride, guanidine hydrochloride
  • a suitable amine e.g., ammonia, ethylamine hydrochloride, guanidine hydrochloride
  • the adenosine derivative is treated with a suitable strong acid or base (e.g., KOH) to form the compounds of formula I.
  • a suitable strong acid or base e.g., KOH
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Examples described herein. However, other equivalent separation or isolation procedures can also be used.
  • the present invention further provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical compositions; the compounds of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes or liposomes.
  • the pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present invention can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-Iipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-Iipophile balance
  • parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of the present invention may be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).
  • the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Suitable carriers and their formulations are further described in A.R. Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995).
  • the compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases, such as mono-, di-, trialkyl, and aryl amines and substituted ethanolamines.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0 0 C and 50 0 C).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides a method for activating an A 2B adenosine receptor in a mammal comprising administering to the mammal an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.
  • the method can further comprise activating an A 2A adenosine receptor upon administration of the compound of formula I.
  • the effective amount can be a therapeutically effective amount or a prophylactically effective amount.
  • the compound can be administered acutely or chronically.
  • the present invention also provides a method for activating an A 2B adenosine receptor in a cell comprising contacting the cell with a compound or pharmaceutically acceptable salt of formula I.
  • the method can further comprise activating an A 2A adenosine receptor upon contacting the cell with a compound of formula I.
  • the method includes contacting the cell and the compound or salt of formula I is carried out in vitro, in vivo, or ex vivo.
  • the term "in vitro” means that the cell is not in a living organism.
  • the term “in vivo” means that the cell is a part of a living organism or is the living organism.
  • ex vivo refers to the administration of a compound to a cell or a population of cells in vitro, followed by administration of the cell or population of cells to a host.
  • the cell is in or from a host.
  • Hosts include, for example, bacteria, yeast, fungi, plants, and mammals.
  • the host is a mammal.
  • mammals include, but are not limited to, the order Rodentia, such as mice, and the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs).
  • the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.
  • the host can be the unborn offspring of any of the forgoing hosts, especially mammals (e.g., humans), in which case any screening of the host or cells of the host, or administration of compounds to the host or cells of the host, can be performed in utero.
  • the amount or dose of a compound of formula I, a salt thereof, or a composition thereof should be sufficient to affect a therapeutic or prophylactic response in the host over a reasonable time frame.
  • the appropriate dose will depend upon the nature and severity of the disease or affliction to be treated or prevented, as well as by other factors. For instance, the dose also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular compound or salt.
  • the attending physician will decide the dosage of the compound of the present invention with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound or salt to be administered, route of administration, and the severity of the condition being treated. Typical doses might be, for example, 0.1 mg to 1 g daily, such as 5 mg to 500 mg daily.
  • the inventive compounds are contemplated to be useful for treating disorders in which therapeutic treatment is effected by activating the A 2B adenosine receptor.
  • the method can further comprise treating disorders in which therapeutic treatment is effected by activating both the A 2A and A 2B adenosine receptors.
  • the present invention contemplates a method of treating or preventing a disorder in a mammal comprising administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof to the mammal, whereupon the disorder is treated or prevented.
  • the disorder is any disorder in which activation of the A 2B or both the A 2B and A 2A adenosine receptors is beneficial in its treatment or prevention.
  • disorders include, for example, septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, and cardiac ischemia.
  • the compounds or pharmaceutically acceptable salts of the invention find use in the preparation of a medicament for activating A 2B adenosine receptors in a mammal.
  • the present invention also provides a method of treating or preventing (a) myocardial ischemia or (b) myocardial ischemia/reperfusion injury in a mammal comprising administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof to the mammal, whereupon the (a) myocardial ischemia or (b) myocardial ischemia/reperfusion injury is treated or prevented.
  • a period of myocardial ischemia followed by reperfusion produces damage to the myocardium.
  • the compound of formula I or a salt thereof is administered for at least the first 24 hrs following reperfusion.
  • the compound of formula I or a salt thereof can limit infarct size when administered at the time of reperfusion. If desired, the compound of formula I or a salt thereof can be administered prior to reperfusion. In a particularly preferred embodiment of this method, the compound administered is 2-(3"-(6"-bromo-indolyl)ethyloxy)adenosine (i.e., compound 28) or a pharmaceutically acceptable salt thereof.
  • the compounds or pharmaceutically acceptable salts of the invention find use in the preparation of a medicament for treating or preventing myocardial ischemia or myocardial ischemia/reperfusion injury.
  • Ischemic preconditioning protects a reperfused heart by inhibiting the formation of permeability transition pores that normally form in many of the heart's mitochondria in the first minutes of reperfusion. These large conductance pores span both the inner and outer membrane and depolarize the matrix which uncouples the mitochondria and halts the oxidative phosphorylation of ADP to ATP. Energy production is thus inhibited at a time when the ischemic cells need it the most. If enough of the cell's mitochondria experience pore formation, then the cell will swell uncontrollably because it lacks the energy required to run the membrane ion pumps that maintain volume control. Those cells suffer lethal membrane rupture and die.
  • Ischemic preconditioning causes activation of ERK and PB -kinase at reperfusion, which ultimately act to inhibit transition pore formation at reperfusion.
  • the signal transduction pathway responsible for the kinase activation in the preconditioned heart includes the A 2B receptor (Kuno et al., J. MoI. Cell. Cardiol, in press (2007)).
  • the untreated heart is reperfused, there are 3 populations of cells present. The first population is killed by the ischemia itself and represents that volume of necrotic tissue seen in the drug- treated groups in Figure 8.
  • the second population includes those cells that have experienced a sub-lethal injury and will recover spontaneously with no treatment. That population represents the surviving tissue seen in the control hearts in Figure 8.
  • the third population represents cells that are still viable at reperfusion but will soon be killed by transition pore formation. It is that population that is salvaged by a drug of formula I (necrotic tissue in the control group minus that in the drug-treated groups in Figure 8).
  • Compounds of formula I that are agonists for both A 2A and A 2B should protect against myocardial ischemia/reperfusion injury.
  • the mammal is a patient prone to reperfusion injury, for example, a patient with coronary artery diseases in general or a patient about to have occluded arteries opened (reperfused) by one or more various interventions (e.g., coronary artery bypass grafts, angioplasty, or thrombolytic therapy).
  • various interventions e.g., coronary artery bypass grafts, angioplasty, or thrombolytic therapy.
  • System A linear gradient solvent system: CH 3 CN/H 2 O from 20/80 to 40/60 in 20 min; the flow rate is 1 mL/min.
  • System B linear gradient solvent system: CH 3 CNZH 2 O from 20/80 to 60/40 in 20 min; the flow rate is 1 mL/min.
  • System C linear gradient solvent system: CH 3 CN/5mM TBAP from 20/80 to 60/40 in 20 min.; the flow rate is 1 mL/min.
  • System D linear gradient solvent system: CH 3 CN/5mM TBAP from 5/95 to 80/20 in 20 min.; the flow rate is 1 mL/min. Peaks are detected by UV absorption with a diode array detector. All derivatives tested for biological activity show >98% purity in the HPLC systems.
  • TLC analysis is carried out on aluminum sheets pre-coated with silica gel F 254 (0.2 mm) from Aldrich.
  • Low-resolution mass spectrometry is performed with a JEOL SXl 02 spectrometer with 6-kV Xe atoms following desorption from a glycerol matrix or on an Agilent LC/MS 1100 MSD, with a Waters (Milford, MA) Atlantis Cl 8 column.
  • High resolution mass spectroscopic (HRMS) measurements are performed on a proteomics optimized Q-TOF-2 (Micromass- Waters) using external calibration using polyalanine. Observed mass accuracies are those expected based on known performance of the instrument as well as trends in masses of standard compounds observed at intervals during the series of measurements. Reported masses are observed masses uncorrected for this time-dependent drift in mass accuracy.
  • binding and functional parameters are calculated using Prism 4.0 software (GraphPAD, San Diego, CA, USA). IC 50 values obtained from competition curves are converted to K; values using the Cheng-Prusoff equation (Cheng et al., Biochem. Pharmacol. 1973, 22, 3099-3108). Data are expressed as mean + standard error.
  • This example demonstrates a general tosylation procedure for the synthesis of 3- iodoethylindole derivatives, 44-46, 56-58, 71-73 and 84 used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2.
  • THF tetrahydrofuran
  • sodium hydride 60 %, 3 eq
  • Tosyl chloride (3 eq) is added to the suspension at 0 °C, and the reaction mixture is stirred at room temperature overnight.
  • reaction mixture is diluted with ethyl acetate and washed with water, dried over MgSO 4 , and filtered. The filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of toluene and acetone (40: 1) gives the desired tosylated derivative.
  • Compound 53 is identical to the known compound reported by Mewshaw et al. (J.
  • Compound 54 is identical to the commercially available compound.
  • This example demonstrates a general synthetic procedure for 3- hydroxyethylindole derivatives (67-70) via Fischer indole ring preparation used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2.
  • a solution of substituted phenylhydrazine hydrochloride and ethoxytetrahydrofuran (1.5 eq) in 95 % ethanol is refluxed overnight.
  • the reaction mixture is filtered through celite.
  • the filtrate is evaporated to give a crude solid.
  • the solid is dissolved in ethyl acetate, and the solution is washed with water, dried over MgSO 4 , and filtered.
  • the filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of toluene and acetone (2:1) gives the alcohol.
  • 6-Chloro-tryptophol (67), 6-Bromo-tryptophol (68), and 5-ChIoro-tryptophol (69) [0096] These compounds are identical to the known compounds. 67: WO 2001/049679;
  • reaction mixture is stirred overnight at room temperature.
  • the reaction is diluted with ethyl acetate, washed with water, dried over MgSO 4 , and filtered.
  • the filtrate is evaporated to give an oil, which is subjected to preparative TLC developed with a mixture of toluene and acetone (1:1) to give 128 (56 mg, 50 %).
  • This example demonstrates a synthesis of 6-guanidino-2-(3"- indolylethyloxy)adenosine (37) and 6-guanidino-2-(3"-(l"-(p- toluenesulfonyl)indolyl)ethyloxy)adenosine (38) in an embodiment of the invention. See Figure 5.
  • CHO Cho et al., Biochem. Pharmacol. 2004, 68, 1985-1993
  • DMEM fetal bovine serum
  • penicillin 100 ⁇ g/mL streptomycin
  • 2 ⁇ mol/mL glutamine 2 ⁇ mol/mL glutamine
  • 800 ⁇ g/mL geneticin 800 ⁇ g/mL geneticin.
  • cells are centrifuged at 500 g for 10 min, and the pellet is re- suspended in 50 mM Tris-HCl buffer (pH 8.0) containing 10 mM MgCl 2 , 1 mM EDTA, and 0.1 mg/mL CHAPS.
  • the suspension is homogenized with an electric homogenizer for 10 sec, and is then re-centrifuged at 20,000 g for 20 min at 4 0 C.
  • the resultant pellets are re- suspended in buffer in the presence of 3 Units/ml adenosine deaminase, and the suspension is stored at -80 0 C until the binding experiments.
  • the protein concentration is measured using the Bradford assay (Bradford et al., Anal. Biochem. 1976, 72, 248-254).
  • [0208] For binding to human A 1 receptors [ 3 H]CCPA (1 nM) is incubated with membranes (40 ⁇ g/tube) from CHO cells stably expressing human Aj receptors at 25 0 C for 60 min in 50 mM Tris-HCl buffer (pH 7.4; MgCl 2 , 10 mM) in a total assay volume of 200 ⁇ L. Nonspecific binding is determined using 10 ⁇ M of CPA.
  • membranes (20 ⁇ g/tube) from HEK-293 cells stably expressing human A 2A receptors are incubated with 15 nM [ 3 H]CGS21680 at 25 0 C for 60 min in 200 ⁇ l 50 mM Tris-HCl, pH 7.4, containing 10 mM MgCl 2 .
  • NECA (10 ⁇ M) is used to define nonspecific binding. The reaction is terminated by filtration with GF/B filters.
  • each tube contains 100 ⁇ L membrane suspension (20 ⁇ g protein), 50 ⁇ L of [ 125 I]I-AB-MECA (0.5 nM), and 50 ⁇ L of increasing concentrations of the nucleoside derivative in Tris-HCl buffer (50 mM, pH 7.4) containing 10 mM MgCl 2 , 1 mM EDTA.
  • Nonspecific binding is determined using 10 ⁇ M of Cl-IB-MECA in the buffer.
  • the mixtures are incubated at 25 0 C for 60 min. Binding reactions are terminated by filtration through Whatman GF/B filters under reduced pressure using a MT-24 cell harvester (Brandell, Gaithersburgh, MD, USA).
  • R 4 C(NH)NH 2
  • R 4 C(NH)NH 2
  • R 2 CONHEt aPotency of various adenosine derivatives in activation of the human A 28 AR expressed in CHO cells, with values expressed either the EC 50 (nM) or the percent stimulation at 10 ⁇ M (in parentheses).
  • binding affinities of the adenosine derivatives at human Ai , A 2A , and A 3 ARs expressed in CHO cells expressed as Kj value or percent displacement at 10 ⁇ M
  • maximal agonist effects at 10 ⁇ M at the A 3 AR Values for compounds 5 - 7 and 9 - 16 are from Gao et al., Biochem. Pharmacol.
  • NECA S'-N-ethylcarboxaminocarbonyladenosine 2 was considered to be the most potent known agonist at the A 2B AR, with an EC 50 of 140 nM (Hide et al., MoI. Pharmacol. 1992, 41, 352-359; Gao et al., Biochem. Pharmacol. 2004, 68, 1985- 1993; and Klotz et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1998, 357, 1-9).
  • Compound 28 is a full agonist at the A 2A and A 2B adenosine receptors.
  • the EC 50 values for 2 are 21.9 nM (A 2 A, Figure 7B) and 110 nM (A 2B , Figure 7C).
  • the EC 50 values of compound 28 are 39.7 nM (A 2A , Figure 7B) and 109 nM (A 2B , Figure 7C) are obtained.
  • the relative maximal efficacy of 28 at the Ai and A 3 adenosine receptors is 31.8% and 20.2 ⁇ 1.0% of the full agonist 2, respectively.
  • Compound 28 is more selective to A 2B adeonosine receptors than compound 2.
  • This example illustrates an anti-infarct effect of compound 28 in an isolated rabbit heart model of ischemia/reperfusion injury in accordance with an embodiment of the invention.
  • New Zealand White rabbits are anesthetized with pentobarbital sodium (30 mg/kg i.v.) and ventilated with 100% oxygen. A suture is passed around a coronary arterial branch.
  • the excised heart is perfused on a Langendorff apparatus with Krebs-Henseleit bicarbonate buffer bubbled with 95% O 2 /5% CO 2 to a pH of 7.35 - 7.45 at 38 0 C.
  • a fluid-filled latex balloon measures pressure in the left ventricle as the heart spontaneously beats in an isometric fashion on the balloon.
  • a prominent branch of the left coronary artery is occluded (regional ischemia) for
  • the percentage of the ischemic region that infarcts in a rabbit heart is a function of the absolute size of the risk zone. Therefore, infarct size is examined by plotting it against the risk zone to make sure that the apparent salvage seen in the drug is not an artifact resulting from smaller risk zones in the treatment group. As shown in Figure 9, a line is fit to the control data with an intercept at about 0.35 cm 3 . This result means that no infarction would occur in an untreated heart with a 30-minute insult if the risk zone is less than 0.35 cm 3 . Figure 9 shows that all of the drug-treated hearts fell well below the line. Thus for any given risk zone volume, the infarcts are clearly smaller in the treated groups.
  • a single high dose (e.g., 160 ⁇ g/kg) bolus plus a continued administration (e.g., 1920 ⁇ g/kg/hr) of compound 28 provides a reduction in the size of the infarcted area.
  • a single high dose (e.g., 160 ⁇ g/kg) bolus plus a continued administration (e.g., 1920 ⁇ g/kg/hr) of compound 28 provides a reduction in the size of the infarcted area.

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Abstract

L'invention concerne des agonistes des récepteurs d'adénosine AZB (AR) de formule (I), R1, R2, R3, R4, Z, et n étant définis dans la présente. L'invention propose également des compositions comprenant au moins un composé de formule I et des procédés pour leur utilisation, par exemple, dans le traitement du choc septique, de la fibrose kystique, de la resténose, de la dysfonction érectile, de l'inflammation, de l'ischémie myocardique, et de la lésion de reperfusion.
PCT/US2008/067978 2007-06-29 2008-06-24 Agonistes des récepteurs d'adénosine a2 WO2009006089A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011133871A3 (fr) * 2010-04-22 2012-03-08 Alnylam Pharmaceuticals, Inc. Dérivés d'extrémité 5'
WO2014024195A1 (fr) * 2012-08-09 2014-02-13 Can-Fite Biopharma Ltd. Ligands du récepteur a3 de l'adénosine pour l'utilisation dans le traitement d'un dysfonctionnement sexuel

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WO1996002553A2 (fr) * 1994-07-14 1996-02-01 Glaxo Group Limited DERIVES AMINO PURINE-β-D-RIBOFURANURONAMIDE

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WO1996002553A2 (fr) * 1994-07-14 1996-02-01 Glaxo Group Limited DERIVES AMINO PURINE-β-D-RIBOFURANURONAMIDE

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ADACHI, H. ET AL.: "Structure-activity relationship of 2,N6,5'-substituted adenosine derivatives with potent activity at the A2B adenosine receptor" J. MED. CHEM., vol. 50, April 2004 (2004-04), pages 1810-1827, XP002504703 *
BARALDI ET AL: "N6-[(Hetero)aryl/(cyclo)alkyl-carbamoyl- methoxy-phenyl]-(2-chloro)- 5'-N-ethylcarboxamido-adenosines: The first example of adenosine-related structures with potent agonist activity at the human A2B adenosine receptor" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 15, no. 7, 12 March 2007 (2007-03-12), pages 2514-2527, XP005922442 ISSN: 0968-0896 *
BARALDI, P.G. ET AL.: "Synthesis and Biological Evaluation of Novel 1-Deoxy-1-[6-[((hetero)arylcarbonyl) hydrazino]- 9H-purin-9-yl]-N-ethyl-?-d-ribo furanuronamide Derivatives as Useful Templates for the Development of A2B Adenosine Receptor Agonists" J. MED. CHEM., vol. 50, 2007, page 374, XP002513993 *
UEEDA M ET AL: "2-Aralkoxyadenosines: potent and selective agonists at the coronary artery A2 adenosine receptor" JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 34, no. 4, 1 April 1991 (1991-04-01), pages 1340-1344, XP002961133 ISSN: 0022-2623 *
ZHAN-GUO GAO ET AL: "2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors" BIOCHEMICAL PHARMACOLOGY, PERGAMON, OXFORD, GB, vol. 68, 2004, pages 1985-1993, XP002453822 ISSN: 0006-2952 cited in the application *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011133871A3 (fr) * 2010-04-22 2012-03-08 Alnylam Pharmaceuticals, Inc. Dérivés d'extrémité 5'
US9725479B2 (en) 2010-04-22 2017-08-08 Ionis Pharmaceuticals, Inc. 5′-end derivatives
WO2014024195A1 (fr) * 2012-08-09 2014-02-13 Can-Fite Biopharma Ltd. Ligands du récepteur a3 de l'adénosine pour l'utilisation dans le traitement d'un dysfonctionnement sexuel
KR20150042232A (ko) * 2012-08-09 2015-04-20 캔-파이트 바이오파마 리미티드 성기능장애의 치료에 사용하기 위한 a3 아데노신 수용체 리간드
AU2013301125B2 (en) * 2012-08-09 2018-03-15 Can-Fite Biopharma Ltd. A3 adenosine receptor ligands for use in treatment of a sexual dysfunction
KR101971762B1 (ko) 2012-08-09 2019-08-13 캔-파이트 바이오파마 리미티드 성기능장애의 치료에 사용하기 위한 a3 아데노신 수용체 리간드
EP3530273A3 (fr) * 2012-08-09 2020-02-26 Can-Fite Biopharma Ltd. Ligands des recepteurs adenosine a3 pour utilisation dans le traitement d'un dysfonctionnement sexuel

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