WO2007064795A2 - Purine derivatives and methods of use thereof - Google Patents

Purine derivatives and methods of use thereof Download PDF

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Publication number
WO2007064795A2
WO2007064795A2 PCT/US2006/045845 US2006045845W WO2007064795A2 WO 2007064795 A2 WO2007064795 A2 WO 2007064795A2 US 2006045845 W US2006045845 W US 2006045845W WO 2007064795 A2 WO2007064795 A2 WO 2007064795A2
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compound
animal
formula
effective amount
pharmaceutically acceptable
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PCT/US2006/045845
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French (fr)
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WO2007064795A3 (en
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Prakash Jagtap
Andrew L. Salzman
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Inotek Pharmaceuticals Corporation
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Priority to CA002627319A priority Critical patent/CA2627319A1/en
Priority to EP06838681A priority patent/EP1962597A4/en
Priority to NZ568392A priority patent/NZ568392A/en
Priority to BRPI0619261-0A priority patent/BRPI0619261A2/en
Priority to AU2006320578A priority patent/AU2006320578B2/en
Priority to JP2008543460A priority patent/JP5203214B2/en
Priority to EA200801467A priority patent/EA015683B1/en
Publication of WO2007064795A2 publication Critical patent/WO2007064795A2/en
Publication of WO2007064795A3 publication Critical patent/WO2007064795A3/en
Priority to NO20082872A priority patent/NO20082872L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular 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
    • A61P9/06—Antiarrhythmics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • the present invention relates to Purine Derivatives; compositions comprising an effective amount of a Purine Derivative; and methods for reducing an animal's core body temperature, protecting an animal's heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
  • Adenosine is a naturally occurring purine nucleoside that is ubiquitous in mammalian cell types. Adenosine exerts its biological effects by interacting with A 1 , A 2 (further subclassified as A 2A and A 2 B) and A 3 cell surface receptors, which modulate important physiological processes.
  • the A 1 and A 2A receptor subtypes are believed to play complementary roles in adenosine's regulation of a cell's energy supply.
  • Adenosine which is a metabolic product of ATP, diffuses from the cell and locally activates the A 1 receptor to decrease the oxygen demand or activates the A 2A receptor to increase the oxygen supply, thereby reinstating the balance of energy supply and demand within the tissue.
  • the combined action OfA 1 and A 2 subtypes increases the amount of available oxygen to tissue and protects cells against damage caused by a short-term imbalance of oxygen.
  • One of the important functions of endogenous adenosine is to prevent tissue damage during traumas such as hypoxia, an ischemic condition, hypotension and seizure activity.
  • Adenosine is also a neuromodulator, which modulates molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects.
  • An increase in neurotransmitter release follows traumas such as hypoxia, ischemia and seizures. Neurotransmitters are ultimately responsible for neural degeneration and neural death, which can cause brain damage or death.
  • Adenosine is thought to be an endogenous anticonvulsant agent that inhibits glutamate release from excitory neurons and neuronal firing. Adenosine agonists, therefore, are useful as antiepileptic agents.
  • Adenosine plays an important role as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischemia and hypoxia and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus are useful as cardioprotective agents.
  • the invention provides compounds having the Formula (I):
  • a and B are trans with respect to each other
  • B and C are cis with respect to each other;
  • C and D are cis or trans with respect to each other;
  • R 1 is -H, -halo, -CN, -N(R 2 ) 2 , -OR 2 , -SR 2 , -NHC(O)R 2 , -NHC(O)N(R 2 ) 2 , -NHC(O)OR 2 , -C(O)OR 2 , -C(O)R 2 , -C(O)N(R 2 ) 2 , -OC(O)N(R 2 ) 2 , -C(halo) 3 , Or -NO 2 ; each R 2 is independently -H, -C 1 -C 1O alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CH 2 ) n -aryl,
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is useful for: (i) treating or preventing a cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes (each being a "Condition”); (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
  • the invention also provides compositions comprising an effective amount of a Purine Derivative and a physiologically acceptable carrier or vehicle.
  • the compositions are useful for: (i) treating or preventing a Condition; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
  • the invention further provides methods for: (i) treating or preventing a
  • Fig 1. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 ⁇ L of 0.3 mg/niL of Compound I'-l;
  • Fig 2. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 ⁇ L of 1.0 mg/mL of Compound I'-l;
  • Fig 3. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 ⁇ L of 3.0 mg/mL of Compound I'-l;
  • Fig 4. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 ⁇ L of 10 mg/mL of Compound I'-l;
  • Fig 5. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 ⁇ L of 30 mg/mL of Compound I'-l.
  • C 1 -C 10 alkyl refers to a straight or branched chain, saturated hydrocarbon having from 1 to 10 carbon atoms.
  • Representative C 1 -C 10 alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, neooctyl, nonyl, isononyl, neononyl, decyl, isodecyl and neodecyl.
  • the C 1 -C 10 alkyl group is substituted with one or more of the following groups: -halo, -0-(Cj-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 1 -C 10 alkyl is uns ⁇ bstituted.
  • C 1 -C 6 alkyl refers to a straight or branched chain, saturated hydrocarbon having from 1 to 6 carbon atoms.
  • Representative C 1 -C 6 alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-bxxty, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl.
  • C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one double bond.
  • Representative C 2 -C 6 alkenyl groups include, but are not limited to, ethylene, propylene, 1 -butyl ene, 2-butylene, isobutylene,
  • the C 2 -C 6 alkenyl group is substituted with one or more of the following groups: -halo, -0-(C 1 -C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or - C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 2 -C 6 alkenyl group is unsubstituted.
  • C 2 -C 6 alkynyl refers to a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one triple bond.
  • Representative C 2 -C 6 alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1- pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne and isohexyne.
  • the C 2 -C 6 alkynyl group is substituted with one or more of the following groups: - halo, -0-(C 1 -C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 2 -C 6 alkynyl group is unsubstituted.
  • aryl refers to a phenyl group or a naphthyl group.
  • the aryl group is substituted with one or more of the following groups: -halo, -0-(C 1 -C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the aryl is unsubstituted.
  • C 3 -C 8 monocyclic cycloalkyl as used herein is a 3-, A-, 5-, 6-, 7- or 8- membered saturated non-aromatic monocyclic cycloalkyl ring.
  • Representative C 3 -C 8 monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the C 3 -C 8 monocyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(C 1 -C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 3 -C 8 monocyclic cycloalkyl is unsubstituted.
  • C 3 -Cs monocyclic cycloalkenyl as used herein is a 3-, A-, 5-, 6-, 7- or 8-membered non-aromatic monocyclic carbocyclic ring having at least one endocyclic double bond, but which is not aromatic. It is to be understood that when any two groups, together with the carbon atom to which they are attached form a C 3 -C 8 monocyclic cycloalkenyl group, the carbon atom to which the two groups are attached remains tetravalent.
  • Representative C 3 -C 8 monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1,3-cyclobutadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl, -1,3,5-cyclooctatrienyl.
  • the C 3 -C 8 monocyclic cycloalkenyl group is substituted with one or more of the following groups: -halo, -0-(C 1 -C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , - NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 3 -C 8 monocyclic cycloalkenyl is unsubstituted.
  • C 8 -C 12 bicyclic cycloalkyl as used herein is a 8-, 9-, 10-, 11- or 12- membered saturated, non-aromatic bicyclic cycloalkyl ring system.
  • Representative C 8 -C 12 bicyclic cycloalkyl groups include, but are not limited to, decahydronaphthalene, octahydroindene, decahydrobenzocycloheptene, and dodecahydroheptalene.
  • the C 8 -C 12 bicyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(C 1 -C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , - NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 8 -C 12 bicyclic cycloalkyl is unsubstituted.
  • C 8 -Ci 2 bicyclic cycloalkenyl as used herein is a 8-, 9-, 10-, 11- or 12- membered non-aromatic bicyclic cycloalkyl ring system, having at least one endocyclic double bond. It is to be understood that when any two groups, together with the carbon atom to which they are attached form a C 8 -C 12 bicyclic cycloalkenyl group, the carbon atom to which the two groups are attached remains tetravalent.
  • Representative C 8 -C 12 bicyclic cycloalkenyl groups include, but are not limited to, octahydronaphthalene, hexahydronaphthalene, hexahydroindene, tetrahydroindene, octahydrobenzocycloheptene, hexahydrobenzocycloheptene, tetrahydrobenzocyclopheptene, decahydroheptalene, octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene.
  • the C 8 -C 12 bicyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(C 1 -C 6 alkyl), -OH, -CN, - COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C 1 -C 6 alkyl. Unless indicated, the C 8 -C 12 bicyclic cycloalkenyl is unsubstituted.
  • an effective amount refers to an amount of a Purine Derivative that is effective for: (i) treating or preventing a Condition; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
  • halo refers to -F, -Cl, -Br or -I.
  • 3- to 7-membered monocyclic heterocycle refers to: (i) a 3- or 4- membered non-aromatic monocyclic cycloalkyl in which 1 of the ring carbon atoms has been replaced with an N, O or S atom; or (ii) a 5-, 6-, or 7-membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the non-aromatic 3- to 7-membered monocyclic heterocycles can be attached via a ring nitrogen, sulfur, or carbon atom.
  • the aromatic 3- to 7-membered monocyclic heterocycles are attached via a ring carbon atom.
  • Representative examples of a 3- to 7-membered monocyclic heterocycle group include, but are not limited to, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazin
  • 8- to 12-membered bicyclic heterocycle refers to a bicyclic 8- to 12- membered aromatic or non-aromatic bicyclic cycloalkyl in which one or both of the of the rings of the bicyclic ring system have 1-4 of its ring carbon atoms independently replaced with a N, O or S atom. Included in this class are 3- to 7-membered monocyclic heterocycles that are fused to a benzene ring.
  • a non-aromatic ring of an 8- to 12-membered monocyclic heterocycle is attached via a ring nitrogen, sulfur, or carbon atom.
  • An aromatic 8- to 12-membered monocyclic heterocycle is attached via a ring carbon atom.
  • Examples of 8- to 12-membered bicyclic heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrzolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, cinnolinyl, decahydroquinolinyl, IH- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoindazolyl, isoindolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, octahydroisoquinolinyl, phthalazinyl, pteridinyl, purinyl, quinoxalin
  • each ring of the 8- to 12-membered bicyclic heterocycle group can substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', - OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the 8- to 12-membered bicyclic heterocycle is unsubstituted.
  • phrases "pharmaceutically acceptable salt,” as used herein, is a salt of an acid and a basic nitrogen atom of a Purine Derivative.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, j5-toluenesulfonate, and pamoate (i.e., l,l'-methylene
  • the pharmaceutically acceptable salt can also be a camphorsulfonate salt.
  • pharmaceutically acceptable salt also refers to a salt of a Purine Derivative having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(
  • the term "pharmaceutically acceptable salt” also includes a hydrate of a Purine Derivative.
  • An "animal” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee or baboon.
  • a monkey is a rhesus.
  • an animal is a human.
  • the term "isolated and purified" as used herein means separate from other components of a reaction mixture or natural source.
  • the isolate contains at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% of a Purine Derivative by weight of the isolate.
  • the isolate contains at least 95% of a Purine Derivative by weight of the isolate.
  • substantially free of its corresponding opposite enantiomer means that a Purine Derivative contains no more than about 10% by weight of its corresponding opposite enantiomer. In one embodiment the Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 5% by weight of its corresponding opposite enantiomer. In a further embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 1% by weight of its corresponding opposite enantiomer. In another embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 0.5% by weight of its corresponding opposite enantiomer. In still another embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 0.1 % by weight of its corresponding opposite enantiomer.
  • substantially free of its corresponding other anomer means that a Purine Derivative contains no more than about 10% by weight of its corresponding other anomer. In one embodiment the Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 5% by weight of its corresponding other anomer. In a further embodiment a Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 1% by weight of its corresponding other anomer. In another embodiment a Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 0.5% by weight of its corresponding other anomer. In still another embodiment a Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 0.1% by weight of its corresponding other anomer.
  • group A is above the plane of the carbon atom to which it is attached and group B is below the plane of the carbon atom to which it is attached. It is to be understood that in group D of the Purine Derivatives of Formula (I), depicted below:
  • the -(CH 2 ) P OH group can be joined at any carbon atom of the
  • ATP is adenosine triphosphate
  • CCPA 2-chloro-N 6 -cyclopentyladenosine
  • CPA is N 6 - cyclopentyladenosine
  • CHO is Chinese hamster ovary
  • Et is ethyl
  • EtOH is ethanol
  • HEK human embryonic kidney
  • LiHMDS is lithium hexamethyldisilazide
  • MeOH is methanol
  • MS mass spectrometry
  • NECA is adenosine-5'-(N-ethyl)carboxamido
  • NMR nuclear magnetic resonance
  • Ph is phenyl
  • R-PIA is N 6 -(2-phenyl-isopropyl) adenosine, R-isomer
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TMSOTf is trimethylsilyl trifluoromethanesulfonate.
  • R 1 is -H.
  • R 1 is -halo
  • R 1 is -Cl.
  • R 1 is -CN.
  • R is -N(R ) 2 .
  • R 1 is -OR 2 .
  • R 1 is -SR 2 .
  • R 1 is -NHC(O)OR 2 , -NHC(O)R 2 , or -NHC(O)N(R 2 ) 2 .
  • R 1 is -C(O)OR 2 , -C(O)R 2 , -C(O)N(R 2 ) 2 , or - OC(O)N(R 2 ) 2 .
  • R 1 is CF 3 .
  • R 1 is -NO 2 .
  • p is 1.
  • p is other than 1.
  • q is 1. In another embodiment, q is 2.
  • q is 3.
  • q is 4.
  • q is 3 or 4.
  • q is 5. In another embodiment, q is 6.
  • R 1 is -H, p is 1 and q is 1. In another embodiment, R 1 is -halo, p is 1 and q is 1. In still another embodiment, R 1 is -Cl, p is 1 and q is 1. In still another embodiment, R 1 is -H or -halo and q is 3 or 4. In still another embodiment, R 1 is -H or -halo, q is 3 or 4 and p is 1.
  • R 1 is -H or -Cl, q is 3 or 4 and p is 1.
  • C and D are cis with respect to each other.
  • C and D are trans with respect to each other.
  • compositions comprising an effective amount of a Purine Derivative of Formula (I) and a physiologically acceptable carrier or vehicle.
  • the invention further provides Purine Derivatives of Formula (I) that are in isolated and purified form.
  • the invention still further provides methods for treating or preventing a Condition, comprising administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.
  • the invention further provides methods for reducing an animal's core body temperature, comprising administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.
  • the invention further provides methods for protecting an animal's heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.
  • a Purine Derivative of Formula (Ia') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ia") when group A of the Purine Derivative of Formula (Ia 1 ) is the same as group A of the Purine Derivative of Formula (Ia") and when group D of the Purine Derivative of Formula (Ia') is the same as group D of the Purine Derivative of Formula (Ia").
  • a Purine Derivative of Formula (Ia") is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ia') when group A of the Purine Derivative of Formula (Ia") is the same as group A of the Purine Derivative of Formula (Ia 1 ) and when group D of the
  • Purine Derivative of Formula (Ia") is the same as group D of the Purine Derivative of Formula (Ia').
  • the Purine Derivatives of Formula (I) have the formula (Ia'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia') are substantially free of their corresponding opposite enantiomer.
  • the Purine Derivatives of Formula (I) have the formula (Ia"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia") are substantially free of their corresponding opposite enantiomer.
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Ia") wherein the amount of the Purine Derivative of Formula (Ia') exceeds the amount of the Purine Derivative of Formula (Ia”).
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Ia") wherein the amount of the Purine Derivative of Formula (Ia") exceeds the amount of the Purine Derivative of Formula (Ia').
  • the Purine Derivatives of Formula (I) exist as a racemic mixture of a Purine Derivative of Formula (Ia 1 ) and a Purine Derivative of Formula (Ia").
  • the Purine Derivatives of Formula (I) can exist in the form of a single enantiomer, for example, that depicted by either formula (Iaa 1 ) or (Iaa”):
  • a Purine Derivative of Formula (Iaa') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iaa") when group A of the Purine Derivative of Formula (Iaa') is the same as group A of the Purine Derivative of Formula (Iaa”) and when group D of the Purine Derivative of Formula (Iaa') is the same as group D of the Purine Derivative of Formula (Iaa”).
  • a Purine Derivative of Formula (Iaa”) is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iaa 1 ) when group A of the Purine Derivative of Formula (Iaa”) is the same as group A of the Purine Derivative of Formula (Iaa') and when group D of the Purine Derivative of Formula (Iaa”) is the same as group D of the Purine Derivative of Formula (Iaa 1 ).
  • the Purine Derivatives of Formula (I) have the formula (Iaa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa') are substantially free of their corresponding opposite enantiomer.
  • the Purine Derivatives of Formula (I) have the formula (Iaa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa') are substantially free of their corresponding opposite enantiomer.
  • the Purine Derivatives of Formula (I) have the formula (Iaa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa') are substantially free of their corresponding opposite enantiomer.
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Iaa 1 ) and a Purine Derivative of Formula (Iaa”) wherein the amount of the Purine Derivative of Formula (Iaa') exceeds the amount of the Purine Derivative of Formula (Iaa”).
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Iaa') and a Purine Derivative of Formula (Iaa”) wherein the amount of the Purine Derivative of Formula (Iaa”) exceeds the amount of the Purine Derivative of Formula (Iaa 1 ).
  • the Purine Derivatives of Formula (I) exist as a racemic mixture of a Purine Derivative of Formula (Iaa') and a Purine Derivative of Formula (Iaa").
  • a Purine Derivative of Formula (Iaa') is the corresponding other anomer of a Purine Derivative of Formula (Ia') when group A of the Purine Derivative of Formula (Iaa') is the same as group A of the Purine Derivative of Formula (Ia') and when group D of the Purine Derivative of Formula (Iaa') is the same as group D of the Purine Derivative of Formula (Ia').
  • a Purine Derivative of Formula (Ia') is the corresponding other anomer of a
  • a Purine Derivative of Formula (Iaa”) is the corresponding other anomer of a Purine Derivative of Formula (Ia") when group A of the Purine Derivative of Formula (Iaa”) is the same as group A of the Purine Derivative of Formula (Ia”) and when group D of the Purine Derivative of Formula (Iaa”) is the same as group D of the Purine Derivative of Formula (Ia”).
  • a Purine Derivative of Formula (Ia”) is the corresponding other anomer of a Purine Derivative of Formula (Iaa”) when group A of the Purine Derivative of Formula (Ia") is the same as group A of the Purine Derivative of Formula (Iaa”) and when group D of the Purine Derivative of Formula (Ia”) is the same as group D of the Purine Derivative of Formula (Iaa”).
  • the Purine Derivatives of Formula (I) have the formula (Iaa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa') are substantially free of their corresponding other anomer.
  • the Purine Derivatives of Formula (I) have the formula (Iaa"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa”) are substantially free of their corresponding other anomer.
  • the Purine Derivatives of Formula (I) have the formula (Ia'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia') are substantially free of their corresponding other anomer.
  • the Purine Derivatives of Formula (I) have the formula (Iaa"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia') are substantially free of their corresponding other anomer.
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Iaa 1 ) wherein the amount of the Purine Derivative of Formula (Ia 1 ) exceeds the amount of the Purine Derivative of Formula (Iaa').
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Iaa') wherein the amount of the Purine Derivative of Formula (Iaa') exceeds the amount of the Purine Derivative of Formula (Ia').
  • the Purine Derivatives of Formula (I) exist as a equal mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Iaa').
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia") and a Purine Derivative of Formula (Iaa”) wherein the amount of the Purine Derivative of Formula (Ia") exceeds the amount of the Purine Derivative of Formula (Iaa”).
  • the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia") and a Purine Derivative of Formula (Iaa”) wherein the amount of the Purine Derivative of Formula (Iaa”) exceeds the amount of the Purine Derivative of Formula (Ia").
  • the Purine Derivatives of Formula (I) exist as a equal mixture of a Purine Derivative of Formula (Ia") and a Purine Derivative of Formula (Iaa”).
  • Illustrative Purine Derivatives of Formula (I) include the compounds of formula (F) as set forth below:
  • Scheme 1 shows methods for making specific stereoisomeric 6-chloroadenosine intermediates that are useful for making the Purine Derviatives of Formula (I).
  • R 1 is as defined above for the Purine Derviatives of Formula (I).
  • the compound of Formula 1 can be coupled with a compound of Formula 2 using lithium hexamethyldisilazide and trimethylsilyl triflate, followed by acetonide removal using trifiuoroacetic acid to provide 6-chloroadenosine intermediates of Formula 3 and their corresponding other anomers of Formula 4.
  • the compound of Formula 5 can be coupled with a compound of Formula 2 using lithium hexamethyldisilazide and trimethylsilyl triflate, followed by acetonide removal using trifiuoroacetic acid to provide compounds of Formula 6 and their corresponding other anomers of Formula 7.
  • Methodology useful for making the Purine Derivatives of Formula (I) is outlined in Scheme 2a.
  • R 1 , p and q are as defined above for the Purine Derivatives of Formula (I).
  • a compound of formula 8a is reacted with a compound of formula 9a in refhixing ethanol to provide the Purine Derivatives of Formula (I).
  • a compound of formula 8b is reacted with a compound of formula 9a in refluxing ethanol to provide the Purine Derivatives of Formula (Y).
  • a variety of compounds 9a, including particular stereoisomers, are commercially available from Acros Organics (Geel, Belgium), AFID Therapeutics Inc. (Lansing, MI), and Sigma-Aldrich (St. Louis, MO).
  • R 1 is — H or -Cl.
  • Scheme 3 sets forth methodology useful for making the compounds of formula 9, wherein p is 1 and q is defined above for the Purine Derivatives of Formula (I).
  • R' is -H or methyl, p is 1 and q is defined above for the Purine Derivatives of Formula (I).
  • a compound of formula 10 is reacted with hydroxylamine in a solvent such as ethanol, and the resultant oxime is reduced, using for example, lithium aluminum hydride, to provide the compounds of formula 9, wherein p is 1 and q is 1, 2, 3, 4, 5 or 6.
  • the compounds of formula 10 are commercially available, or alternatively, can be prepared from commercially available starting materials using methods known to one skilled in the art of organic synthesis.
  • 1,2-substituted keto-esters of formula 10 can be synthesized by reacting a cycloalkanone enolate (prepared from a commercially available cycloalkanone) with an alkyl chloroformate; 1,3 -substituted keto-esters of formula 10 can be synthesized via 1,4 addition to a commercially available conjugated cycloalkenone; and 1,4- substituted keto-esters of formula 10 can be synthesized via oxidation of commercially available 4-carboxylate substituted cycloalkanols.
  • Scheme 4 sets forth methodology useful for making the compounds of formula 9, wherein p is an integer ranging from 3-6 and q is defined above for the Purine Deriviatives of Formula (I).
  • R' is -H or methyl
  • p is an integer ranging from 3 to 6
  • q is defined above for the Purine Derivatives of Formula (I)
  • r is an integer ranging from 0 to 3.
  • a compound of formula 10 is reacted with hydroxylamine, and the resultant oxime is reduced, using for example, diisobutylaluminum hydride (DIBAL), to provide a compound of formula 11.
  • DIBAL diisobutylaluminum hydride
  • the compound of formula 11 can be reacted with a compound of formula 12 via a Wittig reaction to provide a compound of formula 13 (See March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 956-963 (4* ed. 1992)).
  • Scheme 5 sets forth methodology useful for making the amine intermediates of formula 9, wherein p is 2 and q is defined above for the Purine Deriviatives of Formula (I).
  • a compound of formula 15 can be converted to the corresponding amine by reacting 15 with hydroxylamine followed by selective reduction of the resultant oxime using, for example, magnesium in the presence of ammonium formate (See Abiraj et ah, Synth. Commun. 34:599-605 (2004)).
  • a methylene group is then inserted between the the ethyl ester group and the carbocyclic ring of 15 using, for example, a Kowalski ester homologation reaction (Kowalski et ah, J. Am. Chem. Soc. 57:7194 (1992)) to provide a compound of formula 16.
  • the compound of formula 16 can then be reduced to the corresponding alcohol using, for example, lithium aluminum hydride to provide the compounds of formula 9, wherein p is 2 and q is defined above for the Purine Derivatives of Formula (I).
  • the compounds of formula 15 are commercially available, or alternatively, can be prepared from commercially available starting materials using methods known to one skilled in the art of organic synthesis.
  • the Purine Derivatives are advantageously useful in veterinary and human medicine. As described above, the Purine Derivatives are useful for: (i) treating or preventing a Condition in an animal in need thereof; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
  • the Purine Derivatives When administered to an animal, the Purine Derivatives can be administered as a component of a composition that comprises a physiologically acceptable carrier or vehicle.
  • the present compositions, which comprise a Purine Derivative can be administered orally.
  • the Purine Derivatives can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings ⁇ e.g., oral, rectal, or intestinal mucosa) and can be administered together with another biologically active agent. Administration can be systemic or local.
  • Various known delivery systems including encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intraocular, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • administration will result in the release of the Purine Derivatives into the bloodstream.
  • the mode of administration can be left to the discretion of the practitioner.
  • the Purine Derivatives are administered orally. In another embodiment, the Purine Derivatives are administered intravenously.
  • the Purine Derviatives when used to reduce an animal's core body temperature, the Purine Derviatives can be administered by continuous intravenous infusion.
  • the Purine Derivatives can be desirable to administer locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • Ocular administration of the Purine Derivatives can be achieved using an eye-dropper or a contact lens coated or impregnated with the Purine Derivative.
  • the Purine Derivatives into the central nervous system, circulatory system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and by injection adjacent to a peripheral nerve.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the Purine Derivatives can be formulated as a suppository, with traditional binders and carrier or vehicles such as triglycerides.
  • the Purine Derivatives can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Lopez-Berestein et al, Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).
  • the Purine Derivatives can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used.
  • a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med. 321:574 (1989)).
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J Macromol. Sd. Rev. Macromol. Chem. 2:61 (1983); Levy et al, Science 228:190 (1935); During et al, Ann. Neural 25:351 (1989); and Howard et aL, J. Neurosurg. Th 105 (1989)).
  • a controlled- or sustained-release system can be placed in proximity of a target of the Purine Derivatives, e.g., the spinal column, brain, colon, skin, heart, lung, eye, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
  • a target of the Purine Derivatives e.g., the spinal column, brain, colon, skin, heart, lung, eye, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
  • compositions can optionally comprise a suitable amount of a physiologically acceptable carrier or vehicle.
  • physiologically acceptable carriers or vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the physiologically acceptable carriers or vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the physiologically acceptable carriers or vehicles are sterile when administered to an animal. Water can be a particularly useful when the Purine Derivative is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers or vehicles, particularly for injectable solutions.
  • suitable physiologically acceptable carriers or vehicles also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule.
  • suitable physiologically acceptable carrier or vehicles are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example.
  • Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active platform driving a Purine Derivative are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule can be imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • Oral compositions can include standard carriers or vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment the carriers or vehicles are of pharmaceutical grade.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • the compositions' components can be supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water- free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of Purine Derivative.
  • Purine Derivatives are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the Purine Derivatives are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • the Purine Derivatives can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those skilled in the art.
  • Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
  • a controlled- or sustained-release composition comprises a minimal amount of a Purine Derivative to treat or prevent the Condition, reduce an animal's core body temperature or protect an animal's heart against myocardial damage during cardioplegia in a minimal amount of time.
  • Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Purine Derivative, and can thus reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can initially release an amount of a Purine Derivative to treat or prevent the Condition, reduce an animal's core body temperature or protect an animal's heart against myocardial damage during cardioplegia in a minimal amount of time.
  • Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled- or sustained-release compositions can favorably affect the time of onset of action
  • the Purine Derivative that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Purine Derivative to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the Purine Derivative can be released from the dosage form at a rate that will replace the amount of Purine Derivative being metabolized and excreted from the body.
  • Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • Condition reducing an animal's core body temperature, or protecting an animal's heart against myocardial damage during cardioplegia, can be determined by standard clinical techniques.
  • in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of a health-care practitioner. Suitable effective dosage amounts, however, range from about 10 micrograms to about 5 grams about every 4 h, although they are typically about 500 mg or less per every 4 hours.
  • the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours.
  • Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
  • the number and frequency of dosages corresponding to a completed course of therapy can be determined according to the judgment of a health-care practitioner.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one Purine Derivative is administered, the effective dosage amounts correspond to the total amount administered.
  • the amount of a Purine Derivative that is effective for treating or preventing a Condition, or protecting an animal's heart against myocardial damage during cardioplegia typically range from about 0.01 mg/kg to about 100 mg/kg of body weight per day, in one embodiment, from about 0.1 mg/kg to about 50 mg/kg body weight per day, and in another embodiment, from about 1 mg/kg to about 20 mg/kg of body weight per day.
  • the amount of a Purine Derivative that is effective for reducing an animal's core body temperature typically range from about about 1 ⁇ g/kg to about 10 mg/kg, in one embodiment, from about 0.1 mg/kg to about 5 mg/kg body weight per day, and in another embodiment, from about 1 mg/kg to about 2.5 mg/kg of body weight per day.
  • the concentration of the Purine Derivative in the solution that is effective for maintaining the viability of the organ is between about 1 nM to about 1 mM.
  • the Purine Derivatives can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a Condition, reducing an animal's core body temperature, or protecting an animal's heart against myocardial damage during cardioplegia can further comprise administering another therapeutic agent to the animal being administered a Purine Derivative.
  • the other therapeutic agent is administered in an effective amount.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. In one embodiment of the invention, where, another therapeutic agent is administered to an animal, the effective amount of the Purine Derivative is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the Purine Derivatives and the other therapeutic agent act synergistically.
  • the other therapeutic agent is an anti-inflammatory agent.
  • useful anti-inflammatory agents include, but are not limited to, adrenocorticosteroids, such as Cortisol, cortisone, fluorocortisone, prednisone, prednisolone, 6a- methylprednisolone, triamcinolone, betamethasone, and dexamethasone; and non-steroidal antiinflammatory agents (NS AIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and nime
  • the other therapeutic agent is an anti-diabetic agent.
  • useful anti-diabetic agents include, but are not limited to, glucagons; somatostatin; diazoxide; sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, and troglitazone; and ⁇ -glucosidase inhibitors, such as acarbose and miglitol.
  • the other therapeutic agent is an anti-glaucoma agent.
  • anti-glaucoma agents include, but are not limited to, apraclonidine HCl, brimonidine tartrate, dipivefrin HCl, epinephrine HCl, betaxolol HCl, carteolol HCl, levobunolol HCl, metipranolol HCl, timolol, timolol maleate, pilocarpine HCl, pilocarpine, dorzolamide HCl, brinzolamide and latanoprost.
  • the other therapeutic agent is an anti-cardiovascular- disease agent.
  • useful anti-cardiovascular-disease agents include, but are not limited to, carnitine; thiamine; lidocaine; amiodarone; procainamide; mexiletine; bretylium tosylate; propanolol; sotalol; and muscarinic receptor antagonists, such as atropine, scopolamine, homatropine, tropicamide, pirenzipine, ipratropium, tiotropium, and tolterodine.
  • the other therapeutic agent is an analgesic agent.
  • useful analgesic agents include, but are not limited to, buprenorphine, meperidine, morphine, codeine, propoyxphene, fentanyl, sufentanil, etorphine hydrochloride, hydrocodone, hydromorphone, nalbuphine, butorphanol, oxycodone, aspirin, ibuprofen, naproxen sodium, acetaminophen, xylazine, metedomidine, carprofen, naprosin, and pentazocine.
  • the other therapeutic agent is buprenorphine. In another embodiment, the other therapeutic agent is an antiemetic agent.
  • useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, or mixtures thereof.
  • a Purine Derivative and the other therapeutic agent can act additively or, in one embodiment, synergistically.
  • a Purine Derivative is adminsitered concurrently with another therapeutic agent.
  • a composition comprising an effective amount of a Purine Derivative and an effective amount of another therapeutic agent can be administered.
  • a composition comprising an effective amount of a Purine Derivative and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered.
  • an effective amount of a Purine Derivative is administered prior or subsequent to administration of an effective amount of another therapeutic agent.
  • the Purine Derivative is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Purine Derivative exerts its preventative or therapeutic effect for treating or preventing a Condition, reducing an animal's core body temperature or protecting an animal's heart against myocardial damage during cardioplegia.
  • a composition of the invention can be prepared using a method comprising admixing a Purine Derivative and a physiologically acceptable carrier or vehicle. Admixing can be accomplished using methods well known for admixing a compound (or salt) and a physiologically acceptable carrier or vehicle. 4.6 THERAPEUTIC OR PROPHYLACTIC USES OF THE PURINE DERIVATIVES 4.6.1 TREATMENT OR PREVENTION OF A CARDIOVASCULAR DISEASE
  • a cardiovascular disease can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Cardiovascular diseases that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, cardiac transplant, cardioplegia, and a cardiac arrhythmia.
  • the cardiovascular disease is a cardiac arrhythmia, congestive heart failure, circulatory shock or cardiomyopathy.
  • the cardiac arrhythmia is a tachycardia or an an idiotopic arrhythmia.
  • the tachycardia is atrial fibrillation, supraventricular tachycardia, atrial flutter, paroxysmal supraventricular tachycardia, paroxysmal atrial tachycardia, sinus tachycardia, atrioventricular nodal reentry tachycardia, or tachycardia caused by Wolff-Parkinson- White Syndrome.
  • the methods for treating a tachycardia include lowering the animal's cardiac ventricular rate to a rate of not less than about 40 beats per minute. In one embodiment, the methods are useful for lowering an animal's cardiac ventricular rate to a rate of from about 60 beats per minute to about 100 beats per minute. In another embodiment, the methods are useful for lowering an animal's cardiac ventricular rate to a rate of from about 100 beats per minute to about 140 beats per minute.
  • the Purine Derivatives are useful for converting a cardiac arrhythmia to a normal sinus rhythm. Accordingly, the invention encompasses methods for converting a cardiac arrhythmia to a normal sinus rhythm, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
  • the invention provides methods for inducing cardioplegia comprising administering to an animal in need thereof an effective amount of a cardioplegia- inducing agent and a Purine Derivative.
  • Cardioplegia-inducing agents useful in the present invention include, but are not limited to, potassium chloride, procaine, lidocaine, novocaine, bupivocaine, nicorandil, pinacidil, halothane, St. Thomas solution, Fremes solution, 2,3- butanedione monoxime, and esmolol.
  • the cardioplegia-inducing agent is lidocaine.
  • a cardioplegia-inducing agent and a Purine Derivative are present within the same composition.
  • the present methods for inducing cardioplegia are useful for preventing or minimizing myocardial damage from occurring during cardioplegia.
  • the invention provides methods for protecting an animal's heart against myocardial damage during cardioplegia, the method comprising administering to an animal in need thereof an effective amount of a Purine Derivative.
  • the invention provides methods for inducing cardioplegia in an animal while protecting an animal's heart against myocardial damage during the cardioplegia, the method comprising administering to an animal in need thereof an effective amount of:
  • the cardioplegia-inducing agent is administered prior to the administration of the Purine Derivative.
  • Purine Derivative is administered prior to the administration of the cardioplegia-inducing agent.
  • the cardioplegia-inducing agent and the Purine are administered prior to the administration of the cardioplegia-inducing agent.
  • Derivative are administered concurrently.
  • the cardioplegia-inducing agent and the Purine Derivative are administered such that the Purine Derivative exerts its prophylactic effect of protection against myocardial damage while the cardioplegia-inducing agent exerts its cardioplegic effect.
  • a neurological disorder can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Neurological disorders that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, a seizure disorder, such as epilepsy; pain, including acute postoperative pain, cancer pain, neuropathic pain, pain resulting from surgery, labor pain during childbirth, a psychogenic pain syndrome, and headache, including migraine headache and cluster headache; delirium and dementia, such as Lewy body dementia, Alzheimer's disease, Pick's disease, or a Creutzfeldt- Jakob disease; a sleep disorder, such as insomnia, hypersomnia, a sleep apnea syndrome, restless-leg syndrome, or a parasomnia; a cranial nerve disorder, such as Bell's palsy; a disorder of movement, such as tremor, dystonia, Tourette's Syndrome, myoclonus, Huntington's disease, cortico basal degeneration, chorea,
  • the present methods for treating pain further comprise the administration of an additional analgesic agent.
  • the additional analgesic agent is buprenorphine.
  • An ophthalmic condition can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Ophthalmic conditions that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, glaucoma with normal intraocular pressure, glaucoma with intraocular hypertension, pseudoexfoliation syndrome, ischemic retinopathy, diabetic retinopathy, and acute macular degeneration.
  • the neurological disorder treated or prevented is glaucoma with intraocular hypertension or glaucoma with normal intraocular pressure.
  • An ischemic condition can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Ischemic conditions that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, myocardial infarction, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.
  • the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia.
  • a reperfusion injury can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Reperfusion injury can result following a naturally occurring episode, such as a myocardial infarction or stroke, or during a surgical procedure where blood flow in vessels is intentionally or unintentionally blocked.
  • Reperfusion injuries that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, intestinal reperfusion injury, myocardial reperfusion injury; and reperfusion injury resulting from cardiopulmonary bypass surgery, thoracoabdominal aneurysm repair surgery, carotid endaretectomy surgery, or hemorrhagic shock.
  • the reperfusion injury results from cardiopulmonary bypass surgery, thoracoabdominal aneurysm repair surgery, carotid endaretectomy surgery or hemorrhagic shock.
  • Diabetes can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Types of diabetes that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, insulinopathy, diabetes due to pancreatic disease, diabetes associated with another endocrine disease (such as Gushing' s Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by ⁇ -cell toxins.
  • Type I diabetes Insulin Dependent Diabetes Mellitus
  • Type II diabetes Non-Insulin Dependent Diabetes Mellitus
  • gestational diabetes insulinopathy
  • diabetes due to pancreatic disease diabetes associated with another endocrine disease (such as Gushing' s Syndrome, acromegaly, pheochromocytoma
  • the diabetes is Type I diabetes mellitus.
  • the diabetes is Type II diabetes mellitus. 4.6.8 METHODS FORREDUCINGANANIMAL'S CORE BODYTEMPERATURE
  • the invention provides methods for reducing an animal's core body temperature, comprising administering to an animal in need thereof an effective amount of a Purine Derivative.
  • Reducing an animal's core body temperature is useful for slowing metabolism or reducing oxygen consumption, particularly where oxygen delivery to a tissue is inadequate.
  • conditions characterized by inadequate oxygen delivery to a tissue include, but are ⁇ not limited to: (i) a medical procedure, such as heart surgery, brain surgery, organ transplantation, mechanical occlusion of the vascular supply, or vascular stenosis; (ii) a disorder or medical condition such as ischemia, a respiratory disorder, respiratory failure, a pulmonary disorder, anemia, anaphylactic shock, hemmorhagic shock, dehydration, compartment syndrome, intravascular thrombus, septic shock, cystic fibrosis, lung cancer, stroke, a burn, or internal bleeding; (iii) an injury such as drowning, a crush injury to one or more limbs, choking, or suffocation; (iv) a compromised airway due to asthma, a tumor, a lung injury or a tracheal injury; (v) an external compression
  • the present invention encompasses methods for slowing an animal's heart rate during heart surgery; protecting an animal's tissue from damage during surgery, particular heart or brain surgery; reducing intracranial hypertension caused by brain injury in an animal; or inducing hibernation in an animal, each method comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
  • the present invention provides methods for reducing the rate of an animal's oxygen consumption, the method comprising administering to an animal in need thereof an effective amount of a Purine Derivative.
  • Reducing an animal's core body temperature is useful for treating or preventing tissue damage or stroke, resulting from an inadequate supply of oxygen to a cell, a tissue, an organ or an organ system.
  • an animal's core body temperature is reduced to increase emergency recussitation in an injured animal.
  • an animal's core body temperature is reduced prior to and/or during heart surgery.
  • the animal is a human child undergoing pediatric heart surgery.
  • an animal's core body temperature is reduced to treat respiratory failure in an animal.
  • an animal's core body temperature is reduced to aid tissue metabolism in an animal whose respiration and ventilation is facilitated by a ventilator.
  • the animal whose respiration and ventilation is facilitated by a ventilator is a geriatric human.
  • the animal whose respiration and ventilation is facilitated by a ventilator is a premature human infant.
  • an organ can be stored ex vivo in a composition comprising an effective amount of a Purine Derivative.
  • the composition is useful for preserving an organ's viability after being removed from a donor and before the organ is transplanted in a recipient.
  • the donor and recipient are the same.
  • an effective amount of a Purine Derivative can be administered to an animal awaiting organ transplantation to reduce the animal's core body temperature prior to or during organ transplantation.
  • the animal's core body temperature is reduced to a temperature of from about 4 0 C to about 34 0 C.
  • the animal's core body temperature is reduced to about 34 0 C, to about 30 0 C, to about 25 0 C, to about 20 0 C, to about 15 0 C, to about 10 0 C, or to about 4 0 C.
  • an animal's core body temperature is reduced to induce therapeutic hypothermia.
  • Obesity can be treated or prevented by administration of an effective amount of a Purine Derivative.
  • Types of obesity that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, android obesity, gynoid obesity, abdominal obesity, age-related obesity, diet-induced obesity, fat-induced obesity, hypothalamic obesity, morbid obesity, multigenic obesity, and visceral obesity.
  • the obesity is android obesity.
  • the invention provides methods for treating or preventing a wasting disease, comprising administering to an animal in need thereof an effective amount of a Purine Derivative.
  • Types of wasting diseases that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, chronic wasting disease, cancer wasting syndrome, and AIDS wasting syndrome.
  • [ 3 H]NECA was obtained from Du Pont NEN, Dreieich, Germany.
  • Other unlabeled adenosine receptor agonists and antogonists can be obtained from RBI, Natick, Massachusetts.
  • the 96-well microplate filtration system (MultiScreen MAFC) was obtained from Millipore, Eschborn, Germany.
  • Penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), L-glutamine and G- 418 were obtained from Gibco-Life Technologies, Eggenstein, Germany.
  • Other materials can be obtained as described in Klotz et al., J. Biol. Chem., 260:14659-14664, 1985; Lohse et al., Naunyn-Schniedeberg's Arch. Pharmacol, 336:204-210, 1987; and Klotz et al., Naunyn- Schmiedeberg 's Arch. Pharmacol , 357: 1 -9, 1998.
  • NMR nuclear magnetic resonance
  • MS Mass spectral
  • 6-Chloroadenosine (1.145 g, 4 mmol) was diluted with ethanol (50 mL) and to the resultant solution was added 1-hydroxymethylcyclopentylamine (1.0 g, 8 mmol). The resultant reaction mixture was heated to reflux and allowed to stir at reflux for about 15 hours. The resultant reaction mixture was cooled to room temperature, then concentrated in vacuo to ' provide a crude residue. The crude residue was purified using flash column chromatography (silica gel column using 8% methanol-dichloromethane as eluent) to provide Compound I'-l (0.383 gm).
  • 2,6-Dichloroadenosine (0.4 gm, 0.0012 mol) was diluted with ethanol (25 ml) and to the resultant solution was added 1-hydroxymethylcyclopentylamine (1 gm, 0.008 mol). The resultant reaction mixture was heated to reflux and allowed to stir at reflux for about 6 hours. The resultant reaction mixture was then cooled to room temperature and concentrated in vacuo. The resultant residue was purified using flash column chromatography (silica gel column using 8% methanol-dichloromethane eluent) to provide Compound I'-19 (365 mg, 83%).
  • CHO cells stably transfected with human adenosine A 1 receptor were grown and maintained in Dulbecco's Modified Eagles Medium with nutrient mixture F12 (DMEM/F12) without nucleosides, containing 10% fetal calf serum, penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), L-glutamine (2 mM) and Geneticin (G-418, 0.2 mg/mL; A 2B , 0.5 mg/mL) at 37 0 C in 5% CO 2 /95% air. Cells were then split 2 or 3 times weekly at a ratio of between 1:5 and 1 :20.
  • DMEM/F12 Dulbecco's Modified Eagles Medium with nutrient mixture F12
  • Membranes for radioligand binding experiments were prepared from fresh or frozen cells as described in Klotz et al., Naunyn-Schmiedeberg's Arch. Pharmacol, 357:1-9 (1998). The cell suspension was then homogenized in ice-cold hypotonic buffer (5 mM
  • Tris/HCl, 2 mM EDTA, pH 7.4 Tris/HCl, 2 mM EDTA, pH 7.4
  • the membranes were then sedimented from the supernatant for 30 minutes at 100,000 g and resuspended in 50 mM Tris/HCl buffer pH 7.4 (for A 3 adenosine receptors: 50 mM Tris/HCl, 10 mM MgCl 2 , 1 mM EDTA, pH 8.25), frozen in liquid nitrogen at a protein concentration of 1-3 mg/mL and stored at -8O 0 C.
  • the affinities of selected Purine Derivatives for the adenosine A 1 receptor were determined by measuring the displacement of specific [ 3 H] 2-chloro-N 6 -cyclopentyl adenosine (Perkin-Elmer Life Sciences) binding in CHO cells stably transfected with human recombinant A 1 adenosine receptor expressed as Ki (nM).
  • Dissociation constants of unlabeled compounds were determined in competition experiments in 96-well microplates using the A 1 selective agonist 2-chloro-N 6 - [ H]cyclopentyladenosine ([ 3 H]CCPA, InM) for the characterization OfA 1 receptor binding.
  • Nonspecific binding was determined in the presence of 100 ⁇ M R-PIA and 1 mM theophylline, respectively.
  • AU binding data were calculated by non-linear curve fitting using the program SCTFIT (De Lean et al., MoI Pharm. 1982, 21:5-16).
  • mice Male BALB/c mice (6-8 weeks of age) are used in studies investigating lipopolysaccharide-induced cytokine production and survival.
  • cytokine production the mice are treated with an illustrative Purine Derivative (0.03 mg/kg) orally by gavage 30 minutes and are then subjected to lipopolysaccharide (1 mg/kg i.p.) for 90 minutes. After this period blood is taken and serum obtained for analysis. Serum is diluted 1:5 prior to being assayed for cytokines using species-specific ELISA kits (R & D Systems) for the chemokine MIP-I ⁇ and the cytokine TNF- ⁇ levels, which are expressed as pg/mL.
  • species-specific ELISA kits R & D Systems
  • mice can be treated with an illustrative Purine Derivative (oral administration of 0.03 mg/kg) starting 30 minutes prior to the mice being subjected to lipopolysaccharide (55 mg/kg i.p.). The survival of the mice is followed over 72 hours and expressed as a percentage of surviving mice at each time point.
  • an illustrative Purine Derivative oral administration of 0.03 mg/kg starting 30 minutes prior to the mice being subjected to lipopolysaccharide (55 mg/kg i.p.).
  • the survival of the mice is followed over 72 hours and expressed as a percentage of surviving mice at each time point.
  • the thorax is opened, and the heart is rapidly removed and perfused through the ascending aorta using Krebs-Ringer buffer consisting of NaCl (118 mmol/liter), KCl (4.75 mmol/liter), KH 2 PO 4 (1.18 mmol/liter), MgSO 4 (1.18 mmol/liter), CaCl 2 (2.5 mmol/liter), NaHCO 3 (25 mmol/liter), and glucose (11 mmol/liter).
  • a mixture of 95% O 2 and 5% CO 2 at 37 °C is then bubbled through the perfusate (the heart is initially perfused at a constant pressure of 70 mm Hg).
  • perfusion is switched to constant flow perfusion achieved using a micro tube pump.
  • the perfusion pressure is maintained at the same level of constant pressure perfusion by adjusting flow rate. Once the flow rate is determined, it is maintained throughout the experiment.
  • the hearts are stimulated by rectangular pulses at a rate of 5 Hz and 2-millisecond duration and twice the diastolic threshold, delivered from a stimulus isolation unit (ADInstruments Ltd, Australia).
  • Rat hearts are perfused at constant pressure of 70 mmHg without pacing as described above.
  • Bipolar epicardial electrocardiogram (ECG) is recorded by placing two electrodes on the surface of right appendage and apex. A stainless steel cannula is used as an indifferent electrode.
  • the ECG and heart rate are continuously monitored and data are recorded using a PowerLab data acquisition system (ADInstruments Ltd, Australia) in conjunction with a computer, and analyzed using the Chart.3 computer package.
  • ADInstruments Ltd, Australia PowerLab data acquisition system
  • ADInstruments Ltd, Australia PowerLab data acquisition system
  • ligature is released 30 minutes after occlusion.
  • An illustrative Purine Derivative is applied interperfusate 10 minutes before LAD ligation and is present during LAD ligation.
  • An illustrative Purine Derivative is to be tested at 10, 30 and 100 pM concentrations.
  • Rat hearts are initially perfused at a constant pressure of 70 mm Hg using the procedure described above in Example 7. After a 20 minute stabilization period, hearts are subjected to 30 minute no-flow ischemia followed by 40 minute reperfusion. In treated hearts, an illustrative Purine Derivative is infused for 10 minutes prior to induction of ischemia. +dp/dt max is measured after 30 minutes of ischemia followed by 40 minutes of reperfusion to determine the effect on myocardial contractility (dp/dt).
  • mice Male mice (body weight of 25-35 grams) are put into groups as follows: a first group which is to be intreperitoneally administered buprenorphine (0.3 mg/kg), a second group which is to be intreperitoneally administered buprenorphine (1 mg/kg), a third group which is to be intreperitoneally administered an illustrative Purine Derivative (3 mg/kg), a fourth group which is to be intreperitoneally co-administered an illustrative Purine Derivative (3 mg/kg) and buprenorphine (1.0 mg/kg), and a fifth group which is to be intreperitoneally co-administered an illustrative Purine Derivative (3 mg/kg) and buprenorphine (0.3 mg/kg).
  • mice The analgesic effects in mice are measured using an IITC model 33 tail-flick analgesia meter (IITC Inc., Woodland Hills, CA) at 0 minutes (baseline control), 5 minutes, 15 minutes, 30 minutes and 60 minutes (in some cases also 90 and 120 minutes) post-treatment, compound or vehicle treatment. The average recording value of two readings should be used for each time point.
  • a baseline of between 2 — 4 seconds of latency for each mouse and a 10-second cut-off time is set for the maximum possible effect of analgesia (% MPE).
  • mice each having a body weight of 20-30 g are subcutaneously administered 20 ⁇ l of a 1% formalin solution in formaldehyde (prepared by diluting a commercial 4 % [w/v] stock formalin solution) into the dorsal region of their left hind paw.
  • the mice are then assigned to either a control group and administered vehicle, or to a treatment group.
  • Each group is then intraperitoneally administered an illustrative Purine Derivative (1.0 mg/kg). Both groups of animals are then monitored for a reaction for 30 minutes post-treatment to determine how much time each animal spends licking the treated paw.
  • the licking time in control group (vehicle pretreated animals) is then compared to the licking time in the treatment group in order to calculate the analgesic effect.
  • the 30 minute reaction period is divided into two phases: an early phase which lasts from 0 - 5 minutes post-treatment, and a late phase which lasts from 10 - 30 minutes post-treatment.
  • mice (6-8 weeks of age) are intraperitoneally administered streptozotocin (40 mg/kg, once per day for 5 consecutive days) to induce diabetes (blood glucose levels are greater than 200 mg/mL).
  • streptozotocin 40 mg/kg, once per day for 5 consecutive days
  • an •illustrative Purine Derivative (1 mg/kg) into a rear paw and post-treatment allodynia can be measured using an Electrovonfrey anesthesiometer (IITC Inc., Woodland Hills CA 91367).
  • the analgesic activity of an illustrative Purine Derivative is measured at 0 minutes (control), 15 minutes, 30 minutes and 60 minutes time point after administration of an illustrative Purine Derivative.
  • mice Male Wistar rats (each weighing between 200- 250 g, kept under pathogen-free conditions at 24 — 25 0 C and provided with standard rat chow and water ad libitum) are anaesthetized via intraperitoneal administration of pentobarbital (50 mg/kg) and placed in a stereotaxic frame. The atlanto-occipital membrane is exposed and a PE-10 catheter (7.5 cm) is inserted through an incision into the subarachnoidal space. The external end of the catheter is then fixed to the skull, the wound is closed, and the rats are allowed to recover for 7 days post- surgery.
  • pentobarbital 50 mg/kg
  • a Dynamic Plantar Aesthesiometer Ugo Basile, Italy
  • the touch stimulator unit is placed under the animal's paw such that the filament is positioned under the target area of the paw.
  • the filament is then lifted such that it contacted the pad of the animal's paw and continually exerted an increasing upward force on the paw until the animal withdrew the paw.
  • the paw withdrawal threshold is measured 5 times in this manner in turns and the mean of the 5 values is calculated.
  • carrageenan (3%, 100 ⁇ l) is administered subcutaneously into a hindpaw, resulting in marked swelling and redness of the treated paw.
  • the threshold values are measured again.
  • the animals are then divided into a control group (administered vehicle intrathecally) and a treatment group (adminstered an illustrative Purine Derivative intrathecally at in a 10 ⁇ l injection volume). Threshold determinations are repeated as described above at 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after the administration of vehicle or an illustrative Purine Derivative.
  • Male CD rats (each weighing from 220 g to 250 g) are prepared according to the procedure set forth in Z. Seltzer et al, Pain, 43:205 - 218 (1990). The rats are then anesthetized via intraperitoneal administration of sodium pentobarbital (50 mg/kg). A skin incision is made at the upper 1/3 and 2/3 left thigh area of each rat and the left sciatic nerve is exposed and freed from the surrounding connective tissue. An 8-0 nylon suture is then used to tightly ligate the left sciatic nerve of each rat so that the dorsal 1/3 to 1/2 of the nerve thickness is trapped in the ligature. The incision is closed using 4-0 sterile suture.
  • the animals are put into four groups: a first group that is administered vehicle (control group); a second group that is administered an illustrative Purine Derivative at 0.1 mg/kg; a third group that is administered buprenorphine at 0.3 mg/kg; and a fourth group that is coadministered an illustrative Purine Derivative at 0.1 mg/kg and buprenorphine at 0.3 mg/kg.
  • Animals in all four groups are assessed for allodynia immediately prior to treatment and at 10, 20, 30 and 60 minutes post-treatment using the Von Frey Hair test (G.M. Pitcher et al., J Neurosci Methods, 87:185-93 (1999)).
  • JV jugular venus
  • Compound I'-l was dissolved in saline, at concentrations 0.3, 1.0, 3.0, 10.0, and 30.0 mg/mL.
  • One rabbit was administered with each each dose level.
  • One drop (about 100 ⁇ L) of the saline solution of Compound I'-l was applied to the external surface of one eye of each rabbit.
  • Compound I'-l was administered when the level of intraocular pressure was low relative to other timepoints during the day and night. After administration with Compound I'-l, the intraocular pressure did not increase to the normal day values (see Figs. 1-5).
  • Derivative reduces an animal's intraocular pressure and, accordingly, is useful for treating or preventing glaucoma with intraocular hypertension.

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Abstract

The present invention relates to Purine Derivatives; compositions comprising an effective amount of a Purine Derivative; and methods for reducing an animal's core body temperature, protecting an animal's heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.

Description

PURINE DERIVATIVES AND METHODS OF USE THEREOF
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/740,795, filed November 30, 2005, which is incorporated by reference herein in its entirety.
1. FIELD OF THE INVENTION The present invention relates to Purine Derivatives; compositions comprising an effective amount of a Purine Derivative; and methods for reducing an animal's core body temperature, protecting an animal's heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
2. BACKGROUND OF THE INVENTION
Adenosine is a naturally occurring purine nucleoside that is ubiquitous in mammalian cell types. Adenosine exerts its biological effects by interacting with A1, A2 (further subclassified as A2A and A2B) and A3 cell surface receptors, which modulate important physiological processes.
The A1 and A2A receptor subtypes are believed to play complementary roles in adenosine's regulation of a cell's energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and locally activates the A1 receptor to decrease the oxygen demand or activates the A2A receptor to increase the oxygen supply, thereby reinstating the balance of energy supply and demand within the tissue. The combined action OfA1 and A2 subtypes increases the amount of available oxygen to tissue and protects cells against damage caused by a short-term imbalance of oxygen. One of the important functions of endogenous adenosine is to prevent tissue damage during traumas such as hypoxia, an ischemic condition, hypotension and seizure activity.
In addition, modulation OfA1 receptors slows conduction velocity in the heart's atrioventricular node, resulting in the normalization of supraventricular tachycardias and control of cardiac ventricular rate during atrial fibrillation and flutter. Modulation OfA2A receptors also regulates coronary vasodilation. Adenosine is also a neuromodulator, which modulates molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischemia and seizures. Neurotransmitters are ultimately responsible for neural degeneration and neural death, which can cause brain damage or death. Adenosine is thought to be an endogenous anticonvulsant agent that inhibits glutamate release from excitory neurons and neuronal firing. Adenosine agonists, therefore, are useful as antiepileptic agents.
Adenosine plays an important role as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischemia and hypoxia and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus are useful as cardioprotective agents.
The preparation and use of a number of adenosine A1 receptor agonists have been described (Moos et al, J. Med. Chem. 28:1383-1384 (1985); Thompson et al, J. Med. Chem. 34:3388-3390 (1991); Vittori et al, J. Med. Chem. 43 :250-260 (2000); Roelen et al, J Med. Chem, 39;1463-1471 (1996); van der Wenden et al, J Med. Chem. 41 102-108 (1998); Dalpiaz et al., Pharm. Res. 18:531-536 (2001), Beakers et al, J. Med. Chem. 46,1492-1503 (2003); U.S. Patent 5,589,467 to Lau et al; U.S. Patent 5,789,416, to Lum et al; and CE. Muller, Current Medicinal Chemistry 2000, 7, 1269-1288).
The citation of any reference in Section 2 of this application is not an admission that the reference is prior art to this application.
3.1 SUMMARY OF THE INVENTION
In one embodiment, the invention provides compounds having the Formula (I):
Figure imgf000004_0001
(D and pharmaceutically acceptable salts thereof, wherein A is -CH2OH; B and C are -OH; D is:
Figure imgf000005_0001
A and B are trans with respect to each other;
B and C are cis with respect to each other; C and D are cis or trans with respect to each other;
R1 is -H, -halo, -CN, -N(R2)2, -OR2, -SR2, -NHC(O)R2, -NHC(O)N(R2)2, -NHC(O)OR2, -C(O)OR2, -C(O)R2, -C(O)N(R2)2, -OC(O)N(R2)2, -C(halo)3, Or -NO2; each R2 is independently -H, -C1-C1O alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(CH2)n-aryl,
-(CH2)n-(3- to 7-membered monocyclic heterocycle), -(CH2)n-(8- to 12-membered bicyclic heterocycle), -(CH2)n-(C3-C8 monocyclic cycloalkyl), -(CH2)D-(C3-C8 monocyclic cycloalkenyl), -(CH2)H-(C8-C12 bicyclic cycloalkyl), or -(CH2)n-(C8-C12 bicyclic cycloalkenyl); each n is an integer ranging from O to 6; each p is an integer ranging from 1 to 6; and each q is an integer ranging from 1 to 6.
A compound of Formula (I) or a pharmaceutically acceptable salt thereof (a "Purine Derivative") is useful for: (i) treating or preventing a cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes (each being a "Condition"); (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
The invention also provides compositions comprising an effective amount of a Purine Derivative and a physiologically acceptable carrier or vehicle. The compositions are useful for: (i) treating or preventing a Condition; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia. The invention further provides methods for: (i) treating or preventing a
Condition; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
3.2 BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 μL of 0.3 mg/niL of Compound I'-l;
Fig 2. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 μL of 1.0 mg/mL of Compound I'-l;
Fig 3. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 μL of 3.0 mg/mL of Compound I'-l;
Fig 4. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 μL of 10 mg/mL of Compound I'-l; and
Fig 5. depicts measured intraocular pressure in an adult New Zealand White rabbit, prior to (from -25 hours until 0 hours) and following treatment (until 25 hours after treatment) with 100 μL of 30 mg/mL of Compound I'-l.
4. DETAILED DESCRIPTION OF THE INVENTION 4.1 DEFINITIONS
The term "Ci-C10 alkyl" as used herein refers to a straight or branched chain, saturated hydrocarbon having from 1 to 10 carbon atoms. Representative C1-C10 alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, neooctyl, nonyl, isononyl, neononyl, decyl, isodecyl and neodecyl. In one embodiment, the C1-C10 alkyl group is substituted with one or more of the following groups: -halo, -0-(Cj-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C1-C10 alkyl is unsύbstituted.
The term "C1-C6 alkyl" as used herein refers to a straight or branched chain, saturated hydrocarbon having from 1 to 6 carbon atoms. Representative C1-C6 alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-bxxty, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl.
The term "C2-C6 alkenyl" refers to a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one double bond. Representative C2-C6 alkenyl groups include, but are not limited to, ethylene, propylene, 1 -butyl ene, 2-butylene, isobutylene,
■sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene and isohexene. In one embodiment, the C2-C6 alkenyl group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or - C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C2-C6 alkenyl group is unsubstituted.
The term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one triple bond. Representative C2-C6 alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1- pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne and isohexyne. In one embodiment, the C2-C6 alkynyl group is substituted with one or more of the following groups: - halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C2-C6 alkynyl group is unsubstituted.
The term "aryl" as used herein refers to a phenyl group or a naphthyl group. In one embodiment, the aryl group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the aryl is unsubstituted.
The term "C3-C8 monocyclic cycloalkyl" as used herein is a 3-, A-, 5-, 6-, 7- or 8- membered saturated non-aromatic monocyclic cycloalkyl ring. Representative C3-C8 monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In one embodiment, the C3-C8 monocyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C3-C8 monocyclic cycloalkyl is unsubstituted.
The term "C3-Cs monocyclic cycloalkenyl" as used herein is a 3-, A-, 5-, 6-, 7- or 8-membered non-aromatic monocyclic carbocyclic ring having at least one endocyclic double bond, but which is not aromatic. It is to be understood that when any two groups, together with the carbon atom to which they are attached form a C3-C8 monocyclic cycloalkenyl group, the carbon atom to which the two groups are attached remains tetravalent. Representative C3-C8 monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1,3-cyclobutadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl, -1,3,5-cyclooctatrienyl. In one embodiment, the C3-C8 monocyclic cycloalkenyl group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, - NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C3-C8 monocyclic cycloalkenyl is unsubstituted.
The term "C8-C12 bicyclic cycloalkyl" as used herein is a 8-, 9-, 10-, 11- or 12- membered saturated, non-aromatic bicyclic cycloalkyl ring system. Representative C8-C12 bicyclic cycloalkyl groups include, but are not limited to, decahydronaphthalene, octahydroindene, decahydrobenzocycloheptene, and dodecahydroheptalene. In one embodiment, the C8-C12 bicyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, - NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C8-C12 bicyclic cycloalkyl is unsubstituted.
The term "C8-Ci2 bicyclic cycloalkenyl" as used herein is a 8-, 9-, 10-, 11- or 12- membered non-aromatic bicyclic cycloalkyl ring system, having at least one endocyclic double bond. It is to be understood that when any two groups, together with the carbon atom to which they are attached form a C8-C12 bicyclic cycloalkenyl group, the carbon atom to which the two groups are attached remains tetravalent. Representative C8-C12 bicyclic cycloalkenyl groups include, but are not limited to, octahydronaphthalene, hexahydronaphthalene, hexahydroindene, tetrahydroindene, octahydrobenzocycloheptene, hexahydrobenzocycloheptene, tetrahydrobenzocyclopheptene, decahydroheptalene, octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene. In one embodiment, the C8-C12 bicyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, - COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the C8-C12 bicyclic cycloalkenyl is unsubstituted.
The term "effective amount" as used herein refers to an amount of a Purine Derivative that is effective for: (i) treating or preventing a Condition; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
The term "halo" as used herein refers to -F, -Cl, -Br or -I. The term "3- to 7-membered monocyclic heterocycle" refers to: (i) a 3- or 4- membered non-aromatic monocyclic cycloalkyl in which 1 of the ring carbon atoms has been replaced with an N, O or S atom; or (ii) a 5-, 6-, or 7-membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The non-aromatic 3- to 7-membered monocyclic heterocycles can be attached via a ring nitrogen, sulfur, or carbon atom. The aromatic 3- to 7-membered monocyclic heterocycles are attached via a ring carbon atom. Representative examples of a 3- to 7-membered monocyclic heterocycle group include, but are not limited to, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, triazolyl, In one embodiment, the 3- to 7-membered monocyclic heterocycle group is substituted with one or more of the following groups: -halo, -0-(C1-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -C1-C6 alkyl. Unless indicated, the 3- to 7-membered monocyclic heterocycle is unsubstituted.
The term "8- to 12-membered bicyclic heterocycle" refers to a bicyclic 8- to 12- membered aromatic or non-aromatic bicyclic cycloalkyl in which one or both of the of the rings of the bicyclic ring system have 1-4 of its ring carbon atoms independently replaced with a N, O or S atom. Included in this class are 3- to 7-membered monocyclic heterocycles that are fused to a benzene ring. A non-aromatic ring of an 8- to 12-membered monocyclic heterocycle is attached via a ring nitrogen, sulfur, or carbon atom. An aromatic 8- to 12-membered monocyclic heterocycle is attached via a ring carbon atom. Examples of 8- to 12-membered bicyclic heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrzolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, cinnolinyl, decahydroquinolinyl, IH- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoindazolyl, isoindolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, octahydroisoquinolinyl, phthalazinyl, pteridinyl, purinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and xanthenyl. In one embodiment, each ring of the 8- to 12-membered bicyclic heterocycle group can substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', - OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the 8- to 12-membered bicyclic heterocycle is unsubstituted. The phrase "pharmaceutically acceptable salt," as used herein, is a salt of an acid and a basic nitrogen atom of a Purine Derivative. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, j5-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The pharmaceutically acceptable salt can also be a camphorsulfonate salt. The term "pharmaceutically acceptable salt" also refers to a salt of a Purine Derivative having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also includes a hydrate of a Purine Derivative. An "animal" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee or baboon. In one embodiment, a monkey is a rhesus. In another embodiment, an animal is a human.
The term "isolated and purified" as used herein means separate from other components of a reaction mixture or natural source. In certain embodiments, the isolate contains at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% of a Purine Derivative by weight of the isolate. In one embodiment, the isolate contains at least 95% of a Purine Derivative by weight of the isolate. The term "substantially free of its corresponding opposite enantiomer" as used herein, means that a Purine Derivative contains no more than about 10% by weight of its corresponding opposite enantiomer. In one embodiment the Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 5% by weight of its corresponding opposite enantiomer. In a further embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 1% by weight of its corresponding opposite enantiomer. In another embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 0.5% by weight of its corresponding opposite enantiomer. In still another embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 0.1 % by weight of its corresponding opposite enantiomer.
The term "substantially free of its corresponding other anomer" as used herein, means that a Purine Derivative contains no more than about 10% by weight of its corresponding other anomer. In one embodiment the Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 5% by weight of its corresponding other anomer. In a further embodiment a Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 1% by weight of its corresponding other anomer. In another embodiment a Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 0.5% by weight of its corresponding other anomer. In still another embodiment a Purine Derivative that is substantially free of its corresponding other anomer contains no more than about 0.1% by weight of its corresponding other anomer.
Some chemical structures herein are depicted using bold and dashed lines to represent chemical bonds. These bold and dashed lines depict absolute stereochemistry. A bold line indicates that a substituent is above the plane of the carbon atom to which it is attached and a dashed line indicates that a substituent is below the plane of the carbon atom to which it is attached. For example, in the illustration below:
Figure imgf000012_0001
group A is above the plane of the carbon atom to which it is attached and group B is below the plane of the carbon atom to which it is attached. It is to be understood that in group D of the Purine Derivatives of Formula (I), depicted below:
Figure imgf000012_0002
the -(CH2)POH group can be joined at any carbon atom of the
Figure imgf000012_0003
group to which it is attached.
The following abbreviations are used herein and have the indicated definitions: ATP is adenosine triphosphate; CCPA is 2-chloro-N6-cyclopentyladenosine; CPA is N6- cyclopentyladenosine; CHO is Chinese hamster ovary; Et is ethyl; EtOH is ethanol; HEK is human embryonic kidney; LiHMDS is lithium hexamethyldisilazide; MeOH is methanol; MS is mass spectrometry; NECA is adenosine-5'-(N-ethyl)carboxamido; NMR is nuclear magnetic resonance; Ph is phenyl; R-PIA is N6-(2-phenyl-isopropyl) adenosine, R-isomer; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TMSOTf is trimethylsilyl trifluoromethanesulfonate.
4.2 THE PURINE DERIVATIVES 4.2.1 THE PURINE DERIVATIVES OF FORMULA (I)
As stated above, the present invention encompasses Purine Derivatives having the Formula (I):
Figure imgf000013_0001
(D wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and A and
B are trans with respect to each other; B and C are cis with respect to each other; and C and D are cis or trans with respect to each other.
In one embodiment, R1 is -H.
In another embodiment, R1 is -halo.
In a specific embodiment, R1 is -Cl.
In another embodiment, R1 is -CN.
1 0 In still another embodiment, R is -N(R )2.
In yet another embodiment, R1 is -OR2.
In a further embodiment, R1 is -SR2.
In another embodiment, R1 is -NHC(O)OR2, -NHC(O)R2, or -NHC(O)N(R2)2.
In another embodiment, R1 is -C(O)OR2, -C(O)R2, -C(O)N(R2)2, or - OC(O)N(R2)2. In still another embodiment, R1 is CF3.
In yet another embodiment, R1 is -NO2.
In one embodiment, p is 1.
In another embodiment, p is other than 1.
In one embodiment, q is 1. In another embodiment, q is 2.
In still another embodiment, q is 3.
In yet another embodiment, q is 4.
In yet another embodiment, q is 3 or 4.
In a further embodiment, q is 5. In another embodiment, q is 6.
I l In one embodiment, R1 is -H, p is 1 and q is 1. In another embodiment, R1 is -halo, p is 1 and q is 1. In still another embodiment, R1 is -Cl, p is 1 and q is 1. In still another embodiment, R1 is -H or -halo and q is 3 or 4. In still another embodiment, R1 is -H or -halo, q is 3 or 4 and p is 1.
In still another embodiment, R1 is -H or -Cl, q is 3 or 4 and p is 1.
In one embodiment, C and D are cis with respect to each other.
In another embodiment, C and D are trans with respect to each other.
The present invention also provides compositions comprising an effective amount of a Purine Derivative of Formula (I) and a physiologically acceptable carrier or vehicle.
The invention further provides Purine Derivatives of Formula (I) that are in isolated and purified form.
The invention still further provides methods for treating or preventing a Condition, comprising administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.
The invention further provides methods for reducing an animal's core body temperature, comprising administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.
The invention further provides methods for protecting an animal's heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.
The Purine Derivatives of Formula (I) can exist in the form of a single enantiomer, for example, that depicted by either the Formula (Ia') or Formula (Ia"):
Figure imgf000014_0001
(Ia1)
Figure imgf000015_0001
(Ia") wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I).
A Purine Derivative of Formula (Ia') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ia") when group A of the Purine Derivative of Formula (Ia1) is the same as group A of the Purine Derivative of Formula (Ia") and when group D of the Purine Derivative of Formula (Ia') is the same as group D of the Purine Derivative of Formula (Ia").
A Purine Derivative of Formula (Ia") is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ia') when group A of the Purine Derivative of Formula (Ia") is the same as group A of the Purine Derivative of Formula (Ia1) and when group D of the
Purine Derivative of Formula (Ia") is the same as group D of the Purine Derivative of Formula (Ia').
In one embodiment, the Purine Derivatives of Formula (I) have the formula (Ia'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia') are substantially free of their corresponding opposite enantiomer.
In another embodiment, the Purine Derivatives of Formula (I) have the formula (Ia"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia") are substantially free of their corresponding opposite enantiomer.
In another embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Ia") wherein the amount of the Purine Derivative of Formula (Ia') exceeds the amount of the Purine Derivative of Formula (Ia"). In a further embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Ia") wherein the amount of the Purine Derivative of Formula (Ia") exceeds the amount of the Purine Derivative of Formula (Ia').
In another embodiment, the Purine Derivatives of Formula (I) exist as a racemic mixture of a Purine Derivative of Formula (Ia1) and a Purine Derivative of Formula (Ia"). In another embodiment, the Purine Derivatives of Formula (I) can exist in the form of a single enantiomer, for example, that depicted by either formula (Iaa1) or (Iaa"):
Figure imgf000016_0001
(Iaa')
Figure imgf000016_0002
(Iaa") wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I).
A Purine Derivative of Formula (Iaa') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iaa") when group A of the Purine Derivative of Formula (Iaa') is the same as group A of the Purine Derivative of Formula (Iaa") and when group D of the Purine Derivative of Formula (Iaa') is the same as group D of the Purine Derivative of Formula (Iaa").
A Purine Derivative of Formula (Iaa") is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iaa1) when group A of the Purine Derivative of Formula (Iaa") is the same as group A of the Purine Derivative of Formula (Iaa') and when group D of the Purine Derivative of Formula (Iaa") is the same as group D of the Purine Derivative of Formula (Iaa1).
In one embodiment, the Purine Derivatives of Formula (I) have the formula (Iaa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa') are substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of Formula (I) have the formula
(Iaa"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa") are substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Iaa1) and a Purine Derivative of Formula (Iaa") wherein the amount of the Purine Derivative of Formula (Iaa') exceeds the amount of the Purine Derivative of Formula (Iaa"). In a further embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Iaa') and a Purine Derivative of Formula (Iaa") wherein the amount of the Purine Derivative of Formula (Iaa") exceeds the amount of the Purine Derivative of Formula (Iaa1).
In another embodiment, the Purine Derivatives of Formula (I) exist as a racemic mixture of a Purine Derivative of Formula (Iaa') and a Purine Derivative of Formula (Iaa").
A Purine Derivative of Formula (Iaa') is the corresponding other anomer of a Purine Derivative of Formula (Ia') when group A of the Purine Derivative of Formula (Iaa') is the same as group A of the Purine Derivative of Formula (Ia') and when group D of the Purine Derivative of Formula (Iaa') is the same as group D of the Purine Derivative of Formula (Ia'). A Purine Derivative of Formula (Ia') is the corresponding other anomer of a
Purine Derivative of Formula (Iaa') when group A of the Purine Derivative of Formula (Ia') is the same as group A of the Purine Derivative of Formula (Iaa') and when group D of the Purine Derivative of Formula (Ia') is the same as group D of the Purine Derivative of Formula (Iaa').
A Purine Derivative of Formula (Iaa") is the corresponding other anomer of a Purine Derivative of Formula (Ia") when group A of the Purine Derivative of Formula (Iaa") is the same as group A of the Purine Derivative of Formula (Ia") and when group D of the Purine Derivative of Formula (Iaa") is the same as group D of the Purine Derivative of Formula (Ia").
A Purine Derivative of Formula (Ia") is the corresponding other anomer of a Purine Derivative of Formula (Iaa") when group A of the Purine Derivative of Formula (Ia") is the same as group A of the Purine Derivative of Formula (Iaa") and when group D of the Purine Derivative of Formula (Ia") is the same as group D of the Purine Derivative of Formula (Iaa").
In one embodiment, the Purine Derivatives of Formula (I) have the formula (Iaa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa') are substantially free of their corresponding other anomer.
In another embodiment, the Purine Derivatives of Formula (I) have the formula (Iaa"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Iaa") are substantially free of their corresponding other anomer. In one embodiment, the Purine Derivatives of Formula (I) have the formula (Ia'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia') are substantially free of their corresponding other anomer. In another embodiment, the Purine Derivatives of Formula (I) have the formula
(Ia"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of Formula (Ia") are substantially free of their corresponding other anomer.
In one embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Iaa1) wherein the amount of the Purine Derivative of Formula (Ia1) exceeds the amount of the Purine Derivative of Formula (Iaa').
In another embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Iaa') wherein the amount of the Purine Derivative of Formula (Iaa') exceeds the amount of the Purine Derivative of Formula (Ia'). hi a further embodiment, the Purine Derivatives of Formula (I) exist as a equal mixture of a Purine Derivative of Formula (Ia') and a Purine Derivative of Formula (Iaa').
In one embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia") and a Purine Derivative of Formula (Iaa") wherein the amount of the Purine Derivative of Formula (Ia") exceeds the amount of the Purine Derivative of Formula (Iaa").
In another embodiment, the Purine Derivatives of Formula (I) exist as a mixture of a Purine Derivative of Formula (Ia") and a Purine Derivative of Formula (Iaa") wherein the amount of the Purine Derivative of Formula (Iaa") exceeds the amount of the Purine Derivative of Formula (Ia").
In a further embodiment, the Purine Derivatives of Formula (I) exist as a equal mixture of a Purine Derivative of Formula (Ia") and a Purine Derivative of Formula (Iaa").
Illustrative Purine Derivatives of Formula (I) include the compounds of formula (F) as set forth below:
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof.
4.3 METHODS FOR MAKING THE PURINE DERIVATIVES
The Purine Derivatives can be made using the synthetic procedures outlined below in Schemes 1-5.
Scheme 1 shows methods for making specific stereoisomeric 6-chloroadenosine intermediates that are useful for making the Purine Derviatives of Formula (I).
Scheme 1
Figure imgf000038_0002
4
1. LiHMDS, Δ
Figure imgf000038_0004
Figure imgf000038_0003
5 2 6 7 wherein R1 is as defined above for the Purine Derviatives of Formula (I).
The compound of Formula 1 can be coupled with a compound of Formula 2 using lithium hexamethyldisilazide and trimethylsilyl triflate, followed by acetonide removal using trifiuoroacetic acid to provide 6-chloroadenosine intermediates of Formula 3 and their corresponding other anomers of Formula 4. Similarly, the compound of Formula 5 can be coupled with a compound of Formula 2 using lithium hexamethyldisilazide and trimethylsilyl triflate, followed by acetonide removal using trifiuoroacetic acid to provide compounds of Formula 6 and their corresponding other anomers of Formula 7. Methodology useful for making the Purine Derivatives of Formula (I) is outlined in Scheme 2a.
Scheme 2a
Figure imgf000039_0001
8a
Purine Derivatives of Formula (I)
wherein R1, p and q are as defined above for the Purine Derivatives of Formula (I).
A compound of formula 8a is reacted with a compound of formula 9a in refhixing ethanol to provide the Purine Derivatives of Formula (I).
Methodology useful for making the Purine Derivatives of Formula (F) is outlined in Scheme 2b.
Scheme 2b
Figure imgf000039_0002
8b
Purine Derivatives of Formula (I')
wherein R1, p and q are as defined above for the Purine Derivatives of Formula
(I').
A compound of formula 8b is reacted with a compound of formula 9a in refluxing ethanol to provide the Purine Derivatives of Formula (Y). A variety of compounds 9a, including particular stereoisomers, are commercially available from Acros Organics (Geel, Belgium), AFID Therapeutics Inc. (Lansing, MI), and Sigma-Aldrich (St. Louis, MO). In some embodiments, R1 is — H or -Cl.
Scheme 3 sets forth methodology useful for making the compounds of formula 9, wherein p is 1 and q is defined above for the Purine Derivatives of Formula (I).
Scheme 3
Figure imgf000040_0001
Amine intermediates of formula 9 wherein p is 1
wherein R' is -H or methyl, p is 1 and q is defined above for the Purine Derivatives of Formula (I).
A compound of formula 10 is reacted with hydroxylamine in a solvent such as ethanol, and the resultant oxime is reduced, using for example, lithium aluminum hydride, to provide the compounds of formula 9, wherein p is 1 and q is 1, 2, 3, 4, 5 or 6.
The compounds of formula 10 are commercially available, or alternatively, can be prepared from commercially available starting materials using methods known to one skilled in the art of organic synthesis. For example, 1,2-substituted keto-esters of formula 10 can be synthesized by reacting a cycloalkanone enolate (prepared from a commercially available cycloalkanone) with an alkyl chloroformate; 1,3 -substituted keto-esters of formula 10 can be synthesized via 1,4 addition to a commercially available conjugated cycloalkenone; and 1,4- substituted keto-esters of formula 10 can be synthesized via oxidation of commercially available 4-carboxylate substituted cycloalkanols.
Scheme 4 sets forth methodology useful for making the compounds of formula 9, wherein p is an integer ranging from 3-6 and q is defined above for the Purine Deriviatives of Formula (I).
Scheme 4
Figure imgf000041_0001
wherein R' is -H or methyl, p is an integer ranging from 3 to 6, q is defined above for the Purine Derivatives of Formula (I), and r is an integer ranging from 0 to 3.
A compound of formula 10 is reacted with hydroxylamine, and the resultant oxime is reduced, using for example, diisobutylaluminum hydride (DIBAL), to provide a compound of formula 11. The compound of formula 11 can be reacted with a compound of formula 12 via a Wittig reaction to provide a compound of formula 13 (See March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 956-963 (4* ed. 1992)). Hydrogenation of the compound of formula 13, using for example H2 and Pd/C, provides the compound of formula 14, which can then be reduced using, for example, lithium aluminum hydride to provide the compounds of formula 9, wherein p is an integer ranging from 3-6 and q is defined above for the Purine Derivatives of Formula (I).
Scheme 5 sets forth methodology useful for making the amine intermediates of formula 9, wherein p is 2 and q is defined above for the Purine Deriviatives of Formula (I).
Scheme 5
Figure imgf000041_0002
Amine intermediates of formula 9 wherein p is 2 wherein p is an integer ranging from 3 to 6 and q is defined above for the Purine Derivatives of Formula (I).
A compound of formula 15 can be converted to the corresponding amine by reacting 15 with hydroxylamine followed by selective reduction of the resultant oxime using, for example, magnesium in the presence of ammonium formate (See Abiraj et ah, Synth. Commun. 34:599-605 (2004)). A methylene group is then inserted between the the ethyl ester group and the carbocyclic ring of 15 using, for example, a Kowalski ester homologation reaction (Kowalski et ah, J. Am. Chem. Soc. 57:7194 (1992)) to provide a compound of formula 16. The compound of formula 16 can then be reduced to the corresponding alcohol using, for example, lithium aluminum hydride to provide the compounds of formula 9, wherein p is 2 and q is defined above for the Purine Derivatives of Formula (I).
The compounds of formula 15 are commercially available, or alternatively, can be prepared from commercially available starting materials using methods known to one skilled in the art of organic synthesis.
4.4 THERAPEUTIC/PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS OF THE INVENTION
Due to their activity, the Purine Derivatives are advantageously useful in veterinary and human medicine. As described above, the Purine Derivatives are useful for: (i) treating or preventing a Condition in an animal in need thereof; (ii) reducing an animal's core body temperature; or (iii) protecting an animal's heart against myocardial damage during cardioplegia.
When administered to an animal, the Purine Derivatives can be administered as a component of a composition that comprises a physiologically acceptable carrier or vehicle. The present compositions, which comprise a Purine Derivative, can be administered orally. The Purine Derivatives can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings {e.g., oral, rectal, or intestinal mucosa) and can be administered together with another biologically active agent. Administration can be systemic or local. Various known delivery systems, including encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.
Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intraocular, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some instances, administration will result in the release of the Purine Derivatives into the bloodstream. The mode of administration can be left to the discretion of the practitioner.
In one embodiment, the Purine Derivatives are administered orally. In another embodiment, the Purine Derivatives are administered intravenously.
In another embodiment, when the Purine Derivatives are used to reduce an animal's core body temperature, the Purine Derviatives can be administered by continuous intravenous infusion.
In other embodiments, it can be desirable to administer the Purine Derivatives locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In yet other embodiments, it can be desirable to administer the Purine
Derivatives ocularly. Ocular administration of the Purine Derivatives can be achieved using an eye-dropper or a contact lens coated or impregnated with the Purine Derivative.
In certain embodiments, it can be desirable to introduce the Purine Derivatives into the central nervous system, circulatory system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and by injection adjacent to a peripheral nerve. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the Purine Derivatives can be formulated as a suppository, with traditional binders and carrier or vehicles such as triglycerides.
In another embodiment the Purine Derivatives can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Lopez-Berestein et al, Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).
In yet another embodiment the Purine Derivatives can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used. In one embodiment a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med. 321:574 (1989)). In another embodiment polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J Macromol. Sd. Rev. Macromol. Chem. 2:61 (1983); Levy et al, Science 228:190 (1935); During et al, Ann. Neural 25:351 (1989); and Howard et aL, J. Neurosurg. Th 105 (1989)).
In yet another embodiment a controlled- or sustained-release system can be placed in proximity of a target of the Purine Derivatives, e.g., the spinal column, brain, colon, skin, heart, lung, eye, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
The present compositions can optionally comprise a suitable amount of a physiologically acceptable carrier or vehicle. Such physiologically acceptable carriers or vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The physiologically acceptable carriers or vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment the physiologically acceptable carriers or vehicles are sterile when administered to an animal. Water can be a particularly useful when the Purine Derivative is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers or vehicles, particularly for injectable solutions. Suitable physiologically acceptable carriers or vehicles also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment the composition is in the form of a capsule. Other examples of suitable physiologically acceptable carrier or vehicles are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.
In one embodiment the Purine Derivatives are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active platform driving a Purine Derivative are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule can be imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard carriers or vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment the carriers or vehicles are of pharmaceutical grade.
In another embodiment the Purine Derivatives can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. The compositions' components can be supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water- free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of Purine Derivative. Where the Purine Derivatives are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the Purine Derivatives are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. The Purine Derivatives can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those skilled in the art. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
In one embodiment a controlled- or sustained-release composition comprises a minimal amount of a Purine Derivative to treat or prevent the Condition, reduce an animal's core body temperature or protect an animal's heart against myocardial damage during cardioplegia in a minimal amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Purine Derivative, and can thus reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can initially release an amount of a
Purine Derivative that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Purine Derivative to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Purine Derivative in the body, the Purine Derivative can be released from the dosage form at a rate that will replace the amount of Purine Derivative being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. The amount of the Purine Derivative that is effective for treating or preventing a
Condition, reducing an animal's core body temperature, or protecting an animal's heart against myocardial damage during cardioplegia, can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of a health-care practitioner. Suitable effective dosage amounts, however, range from about 10 micrograms to about 5 grams about every 4 h, although they are typically about 500 mg or less per every 4 hours. In one embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The number and frequency of dosages corresponding to a completed course of therapy can be determined according to the judgment of a health-care practitioner. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Purine Derivative is administered, the effective dosage amounts correspond to the total amount administered.
The amount of a Purine Derivative that is effective for treating or preventing a Condition, or protecting an animal's heart against myocardial damage during cardioplegia typically range from about 0.01 mg/kg to about 100 mg/kg of body weight per day, in one embodiment, from about 0.1 mg/kg to about 50 mg/kg body weight per day, and in another embodiment, from about 1 mg/kg to about 20 mg/kg of body weight per day.
The amount of a Purine Derivative that is effective for reducing an animal's core body temperature typically range from about about 1 μg/kg to about 10 mg/kg, in one embodiment, from about 0.1 mg/kg to about 5 mg/kg body weight per day, and in another embodiment, from about 1 mg/kg to about 2.5 mg/kg of body weight per day.
When a Purine Derviative is a component of a solution that is useful for maintaining the viability of an organ ex vivo, the concentration of the Purine Derivative in the solution that is effective for maintaining the viability of the organ is between about 1 nM to about 1 mM.
The Purine Derivatives can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy. The present methods for treating or preventing a Condition, reducing an animal's core body temperature, or protecting an animal's heart against myocardial damage during cardioplegia, can further comprise administering another therapeutic agent to the animal being administered a Purine Derivative. In one embodiment the other therapeutic agent is administered in an effective amount.
Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. In one embodiment of the invention, where, another therapeutic agent is administered to an animal, the effective amount of the Purine Derivative is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the Purine Derivatives and the other therapeutic agent act synergistically.
In one embodiment the other therapeutic agent is an anti-inflammatory agent. Examples of useful anti-inflammatory agents include, but are not limited to, adrenocorticosteroids, such as Cortisol, cortisone, fluorocortisone, prednisone, prednisolone, 6a- methylprednisolone, triamcinolone, betamethasone, and dexamethasone; and non-steroidal antiinflammatory agents (NS AIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and nimesulide.
In another embodiment the other therapeutic agent is an anti-diabetic agent. Examples of useful anti-diabetic agents include, but are not limited to, glucagons; somatostatin; diazoxide; sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, and troglitazone; and α-glucosidase inhibitors, such as acarbose and miglitol.
In another embodiment, the other therapeutic agent is an anti-glaucoma agent. Examples of anti-glaucoma agents include, but are not limited to, apraclonidine HCl, brimonidine tartrate, dipivefrin HCl, epinephrine HCl, betaxolol HCl, carteolol HCl, levobunolol HCl, metipranolol HCl, timolol, timolol maleate, pilocarpine HCl, pilocarpine, dorzolamide HCl, brinzolamide and latanoprost.
In a further embodiment the other therapeutic agent is an anti-cardiovascular- disease agent. Examples of useful anti-cardiovascular-disease agents include, but are not limited to, carnitine; thiamine; lidocaine; amiodarone; procainamide; mexiletine; bretylium tosylate; propanolol; sotalol; and muscarinic receptor antagonists, such as atropine, scopolamine, homatropine, tropicamide, pirenzipine, ipratropium, tiotropium, and tolterodine.
In another embodiment the other therapeutic agent is an analgesic agent. Examples of useful analgesic agents include, but are not limited to, buprenorphine, meperidine, morphine, codeine, propoyxphene, fentanyl, sufentanil, etorphine hydrochloride, hydrocodone, hydromorphone, nalbuphine, butorphanol, oxycodone, aspirin, ibuprofen, naproxen sodium, acetaminophen, xylazine, metedomidine, carprofen, naprosin, and pentazocine.
In a specific embodiment, the other therapeutic agent is buprenorphine. In another embodiment, the other therapeutic agent is an antiemetic agent.
Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, or mixtures thereof.
A Purine Derivative and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, a Purine Derivative is adminsitered concurrently with another therapeutic agent. In one embodiment, a composition comprising an effective amount of a Purine Derivative and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Purine Derivative and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a Purine Derivative is administered prior or subsequent to administration of an effective amount of another therapeutic agent. In this embodiment, the Purine Derivative is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Purine Derivative exerts its preventative or therapeutic effect for treating or preventing a Condition, reducing an animal's core body temperature or protecting an animal's heart against myocardial damage during cardioplegia.
A composition of the invention can be prepared using a method comprising admixing a Purine Derivative and a physiologically acceptable carrier or vehicle. Admixing can be accomplished using methods well known for admixing a compound (or salt) and a physiologically acceptable carrier or vehicle. 4.6 THERAPEUTIC OR PROPHYLACTIC USES OF THE PURINE DERIVATIVES 4.6.1 TREATMENT OR PREVENTION OF A CARDIOVASCULAR DISEASE
A cardiovascular disease can be treated or prevented by administration of an effective amount of a Purine Derivative.
Cardiovascular diseases that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, cardiac transplant, cardioplegia, and a cardiac arrhythmia. In one embodiment, the cardiovascular disease is a cardiac arrhythmia, congestive heart failure, circulatory shock or cardiomyopathy.
In one embodiment, the cardiac arrhythmia is a tachycardia or an an idiotopic arrhythmia.
In still another embodiment, the tachycardia is atrial fibrillation, supraventricular tachycardia, atrial flutter, paroxysmal supraventricular tachycardia, paroxysmal atrial tachycardia, sinus tachycardia, atrioventricular nodal reentry tachycardia, or tachycardia caused by Wolff-Parkinson- White Syndrome.
In a further embodiment, the methods for treating a tachycardia include lowering the animal's cardiac ventricular rate to a rate of not less than about 40 beats per minute. In one embodiment, the methods are useful for lowering an animal's cardiac ventricular rate to a rate of from about 60 beats per minute to about 100 beats per minute. In another embodiment, the methods are useful for lowering an animal's cardiac ventricular rate to a rate of from about 100 beats per minute to about 140 beats per minute.
In another embodiment, the Purine Derivatives are useful for converting a cardiac arrhythmia to a normal sinus rhythm. Accordingly, the invention encompasses methods for converting a cardiac arrhythmia to a normal sinus rhythm, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
4.6.2 PROTECTING AN ANIMAL'S HEART AGAINST MYOCARDIAL DAMAGE DURING CARDIOPLEGIA
In one embodiment, the invention provides methods for inducing cardioplegia comprising administering to an animal in need thereof an effective amount of a cardioplegia- inducing agent and a Purine Derivative. Cardioplegia-inducing agents useful in the present invention include, but are not limited to, potassium chloride, procaine, lidocaine, novocaine, bupivocaine, nicorandil, pinacidil, halothane, St. Thomas solution, Fremes solution, 2,3- butanedione monoxime, and esmolol.
In one embodiment, the cardioplegia-inducing agent is lidocaine.
In one embodiment, a cardioplegia-inducing agent and a Purine Derivative are present within the same composition. The present methods for inducing cardioplegia are useful for preventing or minimizing myocardial damage from occurring during cardioplegia.
In yet another embodiment, the invention provides methods for protecting an animal's heart against myocardial damage during cardioplegia, the method comprising administering to an animal in need thereof an effective amount of a Purine Derivative. In still another embodiment, the invention provides methods for inducing cardioplegia in an animal while protecting an animal's heart against myocardial damage during the cardioplegia, the method comprising administering to an animal in need thereof an effective amount of:
(a) a cardioplegia-inducing agent; and (b) a Purine Derivative.
In one embodiment, the cardioplegia-inducing agent is administered prior to the administration of the Purine Derivative.
In another embodiment, Purine Derivative is administered prior to the administration of the cardioplegia-inducing agent. In a further embodiment, the cardioplegia-inducing agent and the Purine
Derivative are administered concurrently.
In another embodiment, the cardioplegia-inducing agent and the Purine Derivative are administered such that the Purine Derivative exerts its prophylactic effect of protection against myocardial damage while the cardioplegia-inducing agent exerts its cardioplegic effect.
4.6.3 TREATMENT OR PREVENTION OF A NEUROLOGICAL DISORDER
A neurological disorder can be treated or prevented by administration of an effective amount of a Purine Derivative. Neurological disorders that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, a seizure disorder, such as epilepsy; pain, including acute postoperative pain, cancer pain, neuropathic pain, pain resulting from surgery, labor pain during childbirth, a psychogenic pain syndrome, and headache, including migraine headache and cluster headache; delirium and dementia, such as Lewy body dementia, Alzheimer's disease, Pick's disease, or a Creutzfeldt- Jakob disease; a sleep disorder, such as insomnia, hypersomnia, a sleep apnea syndrome, restless-leg syndrome, or a parasomnia; a cranial nerve disorder, such as Bell's palsy; a disorder of movement, such as tremor, dystonia, Tourette's Syndrome, myoclonus, Huntington's disease, cortico basal degeneration, chorea, a drug-induced movement disorder, progressive supranuclear palsy, Parkinson's disease, or a Parkinsonian Syndrome, such as multiple system atrophy, Wilson's disease or mult-infarct state; a demyelinating disease, such as multiple sclerosis or amyotrophic lateral sclerosis; a neuromuscular disease, such as muscular dystrophy; a cerebrovascular disease, such as stroke; a neuroopthalmic disorder; a psychiatric disorder, including but not limited to, a somatoform disorder, such as hypochondriasis or body dysmorphic disorder; a dissociation disorder, such as panic disorder, a phobic disorder, or an obsessive-compulsive disorder; a mood disorder, such as depression or a bipolar disorder; a personality disorder; a psychosexual disorder; suicidal behavior; schizophrenia; brief psychotic disorder; and delusional disorder. In one embodiment, the neurological disorder treated or prevented is epilepsy, pain, or stroke.
In one embodiment, the present methods for treating pain further comprise the administration of an additional analgesic agent. In a specific embodiment, the additional analgesic agent is buprenorphine.
4.6.4 TREATMENT OR PREVENTION OF AN OPHTHALMIC CONDITION An ophthalmic condition can be treated or prevented by administration of an effective amount of a Purine Derivative.
Ophthalmic conditions that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, glaucoma with normal intraocular pressure, glaucoma with intraocular hypertension, pseudoexfoliation syndrome, ischemic retinopathy, diabetic retinopathy, and acute macular degeneration.
In one embodiment, the neurological disorder treated or prevented is glaucoma with intraocular hypertension or glaucoma with normal intraocular pressure.
4.6.5 TREATMENT OR PREVENTION OF AN ISCHEMIC CONDITION An ischemic condition can be treated or prevented by administration of an effective amount of a Purine Derivative.
Ischemic conditions that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, myocardial infarction, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.
In one embodiment, the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia.
4.6.6 TREATMENT OR PREVENTION OF A REPERFUSION INJURY A reperfusion injury can be treated or prevented by administration of an effective amount of a Purine Derivative. Reperfusion injury can result following a naturally occurring episode, such as a myocardial infarction or stroke, or during a surgical procedure where blood flow in vessels is intentionally or unintentionally blocked.
Reperfusion injuries that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, intestinal reperfusion injury, myocardial reperfusion injury; and reperfusion injury resulting from cardiopulmonary bypass surgery, thoracoabdominal aneurysm repair surgery, carotid endaretectomy surgery, or hemorrhagic shock.
In one embodiment, the reperfusion injury results from cardiopulmonary bypass surgery, thoracoabdominal aneurysm repair surgery, carotid endaretectomy surgery or hemorrhagic shock.
4.6.7 TREATMENT OR PREVENTION OF DIABETES
Diabetes can be treated or prevented by administration of an effective amount of a Purine Derivative.
Types of diabetes that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, insulinopathy, diabetes due to pancreatic disease, diabetes associated with another endocrine disease (such as Gushing' s Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by β-cell toxins.
In one embodiment, the diabetes is Type I diabetes mellitus.
In another embodiment, the diabetes is Type II diabetes mellitus. 4.6.8 METHODS FORREDUCINGANANIMAL'S CORE BODYTEMPERATURE
In one embodiment, the invention provides methods for reducing an animal's core body temperature, comprising administering to an animal in need thereof an effective amount of a Purine Derivative.
Reducing an animal's core body temperature is useful for slowing metabolism or reducing oxygen consumption, particularly where oxygen delivery to a tissue is inadequate. Examples of conditions characterized by inadequate oxygen delivery to a tissue include, but are ■ not limited to: (i) a medical procedure, such as heart surgery, brain surgery, organ transplantation, mechanical occlusion of the vascular supply, or vascular stenosis; (ii) a disorder or medical condition such as ischemia, a respiratory disorder, respiratory failure, a pulmonary disorder, anemia, anaphylactic shock, hemmorhagic shock, dehydration, compartment syndrome, intravascular thrombus, septic shock, cystic fibrosis, lung cancer, stroke, a burn, or internal bleeding; (iii) an injury such as drowning, a crush injury to one or more limbs, choking, or suffocation; (iv) a compromised airway due to asthma, a tumor, a lung injury or a tracheal injury; (v) an external compression of one or more blood vessels; or (vi) an intrinsic obstruction of one or more blood vessels.
Accordingly, the present invention encompasses methods for slowing an animal's heart rate during heart surgery; protecting an animal's tissue from damage during surgery, particular heart or brain surgery; reducing intracranial hypertension caused by brain injury in an animal; or inducing hibernation in an animal, each method comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
Reducing an animal's core body temperature is also useful for reducing an animal's rate of oxygen consumption. Accordingly, the present invention provides methods for reducing the rate of an animal's oxygen consumption, the method comprising administering to an animal in need thereof an effective amount of a Purine Derivative.
Reducing an animal's core body temperature is useful for treating or preventing tissue damage or stroke, resulting from an inadequate supply of oxygen to a cell, a tissue, an organ or an organ system. In one embodiment, an animal's core body temperature is reduced to increase emergency recussitation in an injured animal.
In another embodiment, an animal's core body temperature is reduced prior to and/or during heart surgery. In a specific embodiment, the animal is a human child undergoing pediatric heart surgery. In another embodiment, an animal's core body temperature is reduced to treat respiratory failure in an animal.
In one embodiment, an animal's core body temperature is reduced to aid tissue metabolism in an animal whose respiration and ventilation is facilitated by a ventilator. In a specific embodiment, the animal whose respiration and ventilation is facilitated by a ventilator is a geriatric human. In another specific embodiment, the animal whose respiration and ventilation is facilitated by a ventilator is a premature human infant.
In one embodiment, an organ can be stored ex vivo in a composition comprising an effective amount of a Purine Derivative. The composition is useful for preserving an organ's viability after being removed from a donor and before the organ is transplanted in a recipient. In one embodiment, the donor and recipient are the same.
In another embodiment, an effective amount of a Purine Derivative can be administered to an animal awaiting organ transplantation to reduce the animal's core body temperature prior to or during organ transplantation. In one embodiment, the animal's core body temperature is reduced to a temperature of from about 4 0C to about 340C. In certain embodiments, the animal's core body temperature is reduced to about 34 0C, to about 30 0C, to about 25 0C, to about 20 0C, to about 15 0C, to about 10 0C, or to about 4 0C.
In a specific embodiment, an animal's core body temperature is reduced to induce therapeutic hypothermia.
4.6.9 TREATMENT OR PREVENTION OF OBESITY
Obesity can be treated or prevented by administration of an effective amount of a Purine Derivative. Types of obesity that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, android obesity, gynoid obesity, abdominal obesity, age-related obesity, diet-induced obesity, fat-induced obesity, hypothalamic obesity, morbid obesity, multigenic obesity, and visceral obesity. In one embodiment, the obesity is android obesity.
4.6.10 TREATMENT OR PREVENTION OF A WASTING DISEASE
In one embodiment, the invention provides methods for treating or preventing a wasting disease, comprising administering to an animal in need thereof an effective amount of a Purine Derivative. Types of wasting diseases that can be treated or prevented by administering an effective amount of a Purine Derivative include, but are not limited to, chronic wasting disease, cancer wasting syndrome, and AIDS wasting syndrome.
The following examples are set forth to assist in understanding the invention and should not, of course, be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
5. EXAMPLES
Materials: [3H]NECA was obtained from Du Pont NEN, Dreieich, Germany. Other unlabeled adenosine receptor agonists and antogonists can be obtained from RBI, Natick, Massachusetts. The 96-well microplate filtration system (MultiScreen MAFC) was obtained from Millipore, Eschborn, Germany. Penicillin (100 U/mL), streptomycin (100 μg/mL), L-glutamine and G- 418 were obtained from Gibco-Life Technologies, Eggenstein, Germany. Other materials can be obtained as described in Klotz et al., J. Biol. Chem., 260:14659-14664, 1985; Lohse et al., Naunyn-Schniedeberg's Arch. Pharmacol, 336:204-210, 1987; and Klotz et al., Naunyn- Schmiedeberg 's Arch. Pharmacol , 357: 1 -9, 1998.
General Methods: Proton nuclear magnetic resonance (NMR) spectra were obtained from Varian 300 MHz spectrophotometer and chemical shifts are reported in parts per million. Compounds were characterized on the basis of NMR and Mass spectral (MS) data. 6- Chloroadenosine and 2,6-dichloroadenosine were purchased from TRC, Ontario, Canada, ACROS Organic, USA, or Sigma-Aldrich (St. Loius, MO).
5.1 Example 1 Preparation of Compound I'-l
Figure imgf000057_0001
r-i
6-Chloroadenosine (1.145 g, 4 mmol) was diluted with ethanol (50 mL) and to the resultant solution was added 1-hydroxymethylcyclopentylamine (1.0 g, 8 mmol). The resultant reaction mixture was heated to reflux and allowed to stir at reflux for about 15 hours. The resultant reaction mixture was cooled to room temperature, then concentrated in vacuo to ' provide a crude residue. The crude residue was purified using flash column chromatography (silica gel column using 8% methanol-dichloromethane as eluent) to provide Compound I'-l (0.383 gm). 1H NMR (DMSO-d6): δ 1.51 - 1.62 (m, 2H), 1.7 - 1.82 (m, 4H), 2.10 - 2.18 (m, 2H), 3.16 (d, J = 5.1 Hz, IH), 3.50 - 3.58 (m, IH), 3.62 - 3.68 (m, 2H), 3.95 (bs, IH), 4.09 - 4.15 (m, IH), 4.58 - 4.66 (m, IH), 5.06 - 5.10 (m, IH), 5.18 (d, J - 4.2 Hz, IH), 5.35 - 5.40 (m, IH), 5.44 (d, J = 6 Hz, IH), 5.87 (d, J = 6 Hz, IH), 6.85 (s, IH), 8.20 (s, IH), 8.36 (s, IH); MS (ES+): m/z 366 (M+l).
5.2 Example 2
Preparation of Compound I'-19
Figure imgf000057_0002
r-19
2,6-Dichloroadenosine (0.4 gm, 0.0012 mol) was diluted with ethanol (25 ml) and to the resultant solution was added 1-hydroxymethylcyclopentylamine (1 gm, 0.008 mol). The resultant reaction mixture was heated to reflux and allowed to stir at reflux for about 6 hours. The resultant reaction mixture was then cooled to room temperature and concentrated in vacuo. The resultant residue was purified using flash column chromatography (silica gel column using 8% methanol-dichloromethane eluent) to provide Compound I'-19 (365 mg, 83%). 1H NMR (DMSO-de): δ 1.51 - 1.62 (m, 2H), 1.71 - 1.82 (m, 4H), 2.10 - 2.18 (m, 2H)5 3.50 - 3.58 (m, IH), 3.62 - 3.65 (m, 2H), 3.94 (bs, IH), 4.12 (bs, IH), 4.51 (d, J = 5.4 Hz, IH), 4.97 (bs, IH), 5.07 - 5.09 (m, IH), 5.22 - 5.24 (m, IH), 5.48 - 5.50 (m, IH), 5.77 (d, J = 2.4 Hz, IH), 5.80 - 5.82 (m, IH), 7.42 (s, IH), 8.40 (s, IH); MS (ES+): m/z 400 (M+l).
5.3 Example 3
Preparation of Compounds I'-7, 1'-91a, I'-92a, I'-92b, I'-93a, F-94a, I'-95a, and I'-95b
Compounds I'-7, F-91a, F-92a, F-92b, I'-93a, F-94a, F-95a, and F-95b were prepared according to the general methodology described in Examples 1 and 2 and elsewhere herein. These compounds were characterized by mass spectroscopy as set forth in Table 1 below.
Table 1
Mass spectroscopic characterization for illustrative Purine Derivatives
Figure imgf000058_0001
5.4 Example 4
Cell Culture and Membrane Preparation For Adenosine Receptor Binding Studies
CHO cells stably transfected with human adenosine A1 receptor were grown and maintained in Dulbecco's Modified Eagles Medium with nutrient mixture F12 (DMEM/F12) without nucleosides, containing 10% fetal calf serum, penicillin (100 U/mL), streptomycin (100 μg/mL), L-glutamine (2 mM) and Geneticin (G-418, 0.2 mg/mL; A2B, 0.5 mg/mL) at 370C in 5% CO2/95% air. Cells were then split 2 or 3 times weekly at a ratio of between 1:5 and 1 :20.
Membranes for radioligand binding experiments were prepared from fresh or frozen cells as described in Klotz et al., Naunyn-Schmiedeberg's Arch. Pharmacol, 357:1-9 (1998). The cell suspension was then homogenized in ice-cold hypotonic buffer (5 mM
Tris/HCl, 2 mM EDTA, pH 7.4) and the resultant homogenate was spun for 10 minutes (40C) at 1,000 g. The membranes were then sedimented from the supernatant for 30 minutes at 100,000 g and resuspended in 50 mM Tris/HCl buffer pH 7.4 (for A3 adenosine receptors: 50 mM Tris/HCl, 10 mM MgCl2, 1 mM EDTA, pH 8.25), frozen in liquid nitrogen at a protein concentration of 1-3 mg/mL and stored at -8O0C.
5.5 Example 5 Adenosine Receptor Binding Studies
The affinities of selected Purine Derivatives for the adenosine A1 receptor were determined by measuring the displacement of specific [3H] 2-chloro-N6-cyclopentyl adenosine (Perkin-Elmer Life Sciences) binding in CHO cells stably transfected with human recombinant A1 adenosine receptor expressed as Ki (nM).
Dissociation constants of unlabeled compounds (K;-values) were determined in competition experiments in 96-well microplates using the A1 selective agonist 2-chloro-N6- [ H]cyclopentyladenosine ([3H]CCPA, InM) for the characterization OfA1 receptor binding. Nonspecific binding was determined in the presence of 100 μM R-PIA and 1 mM theophylline, respectively. For details see Klotz et al., Naunyn-Schmiedeberg's Arch. Pharmacol, 357:1-9, 1998. AU binding data were calculated by non-linear curve fitting using the program SCTFIT (De Lean et al., MoI Pharm. 1982, 21:5-16).
Results are presented in Table 2 below. Table 2
Affinities of illustrative Purine Derivatives for human A1, A2A and A3 adenosine receptors
Figure imgf000060_0001
displacement of specific [3H]CCPA binding in CHO cells stably transfected with human recombinant Ai adenosine receptor, expressed as Ki (nM). bDisplacement of specific [3H]NECA binding in CHO cells stably transfected with human recombinant A2A adenosine receptor, expressed as Ki (nM). displacement of specific [3H]NECA binding in HEK cells stably transfected with human recombinant A3 adenosine receptor, expressed as Kx (nM). AU data are geometric means with 95% confidence intervals in parentheses.
The data set forth in Table 2 demonstrate that Compounds I'-l and F-9, illustrative Purine Derivatives, selectively bind the adenosine A1 receptor and accordingly, are useful for treating or preventing a Condition, slowing an animal's metabolic rate, or protecting an animal's heart against myocardial damage during cardioplegia.
5.6 Example 6 Determination of the Effects of the Purine Derivatives on septic shock
Male BALB/c mice (6-8 weeks of age) are used in studies investigating lipopolysaccharide-induced cytokine production and survival. For cytokine production the mice are treated with an illustrative Purine Derivative (0.03 mg/kg) orally by gavage 30 minutes and are then subjected to lipopolysaccharide (1 mg/kg i.p.) for 90 minutes. After this period blood is taken and serum obtained for analysis. Serum is diluted 1:5 prior to being assayed for cytokines using species-specific ELISA kits (R & D Systems) for the chemokine MIP-I α and the cytokine TNF-α levels, which are expressed as pg/mL. For survival studies mice can be treated with an illustrative Purine Derivative (oral administration of 0.03 mg/kg) starting 30 minutes prior to the mice being subjected to lipopolysaccharide (55 mg/kg i.p.). The survival of the mice is followed over 72 hours and expressed as a percentage of surviving mice at each time point.
5.7 Example 7 Determination of the Anti-arrhythmia effects of the Purine Derivatives
Heart perfusion Male Sprague-Dawley rats (having a body weight of 250 to 300 g) are heparinized using sodium heparin (1,000 U/kg i.p.), followed 10 minutes later by introduction of anesthesia via intraperitoneal administration of sodium pentobarbital (40 mg/kg). Once the animal is anesthetized, the thorax is opened, and the heart is rapidly removed and perfused through the ascending aorta using Krebs-Ringer buffer consisting of NaCl (118 mmol/liter), KCl (4.75 mmol/liter), KH2PO4 (1.18 mmol/liter), MgSO4 (1.18 mmol/liter), CaCl2 (2.5 mmol/liter), NaHCO3 (25 mmol/liter), and glucose (11 mmol/liter). A mixture of 95% O2 and 5% CO2 at 37 °C is then bubbled through the perfusate (the heart is initially perfused at a constant pressure of 70 mm Hg). About 10 minutes after the constant pressure perfusion, perfusion is switched to constant flow perfusion achieved using a micro tube pump. The perfusion pressure is maintained at the same level of constant pressure perfusion by adjusting flow rate. Once the flow rate is determined, it is maintained throughout the experiment. The hearts are stimulated by rectangular pulses at a rate of 5 Hz and 2-millisecond duration and twice the diastolic threshold, delivered from a stimulus isolation unit (ADInstruments Ltd, Australia).
Effect of the Purine Derivatives on ischemia-induced arrhythmias
Rat hearts are perfused at constant pressure of 70 mmHg without pacing as described above. Bipolar epicardial electrocardiogram (ECG) is recorded by placing two electrodes on the surface of right appendage and apex. A stainless steel cannula is used as an indifferent electrode. The ECG and heart rate are continuously monitored and data are recorded using a PowerLab data acquisition system (ADInstruments Ltd, Australia) in conjunction with a computer, and analyzed using the Chart.3 computer package. After a 20-minute equilibration period, regional ischemia is induced by ligation of the left anterior descending (LAD) coronary artery, and the ligature is released 30 minutes after occlusion. An illustrative Purine Derivative is applied interperfusate 10 minutes before LAD ligation and is present during LAD ligation. An illustrative Purine Derivative is to be tested at 10, 30 and 100 pM concentrations.
5.8 Example 8
Determination of the Effect of the Purine Derivatives on function recovery after global ischemia/reperfusion
Effect of an illustrative Purine Derivative on function recovery after ischemia/reperfusion Rat hearts are initially perfused at a constant pressure of 70 mm Hg using the procedure described above in Example 7. After a 20 minute stabilization period, hearts are subjected to 30 minute no-flow ischemia followed by 40 minute reperfusion. In treated hearts, an illustrative Purine Derivative is infused for 10 minutes prior to induction of ischemia. +dp/dtmax is measured after 30 minutes of ischemia followed by 40 minutes of reperfusion to determine the effect on myocardial contractility (dp/dt).
5.9 Example 9 Determination of the Effect of the Purine Derivatives on Pain
Male mice (body weight of 25-35 grams) are put into groups as follows: a first group which is to be intreperitoneally administered buprenorphine (0.3 mg/kg), a second group which is to be intreperitoneally administered buprenorphine (1 mg/kg), a third group which is to be intreperitoneally administered an illustrative Purine Derivative (3 mg/kg), a fourth group which is to be intreperitoneally co-administered an illustrative Purine Derivative (3 mg/kg) and buprenorphine (1.0 mg/kg), and a fifth group which is to be intreperitoneally co-administered an illustrative Purine Derivative (3 mg/kg) and buprenorphine (0.3 mg/kg). The analgesic effects in mice are measured using an IITC model 33 tail-flick analgesia meter (IITC Inc., Woodland Hills, CA) at 0 minutes (baseline control), 5 minutes, 15 minutes, 30 minutes and 60 minutes (in some cases also 90 and 120 minutes) post-treatment, compound or vehicle treatment. The average recording value of two readings should be used for each time point. A baseline of between 2 — 4 seconds of latency for each mouse and a 10-second cut-off time is set for the maximum possible effect of analgesia (% MPE). % MPE is calculated using the following formula: %MPE = [(post-drug value - baseline) / (cut-off time - baseline)] x 100.
5.10 Example 10 Determination of the Effect of the Purine Derivatives on Pain
Male mice (each having a body weight of 20-30 g) are subcutaneously administered 20 μl of a 1% formalin solution in formaldehyde (prepared by diluting a commercial 4 % [w/v] stock formalin solution) into the dorsal region of their left hind paw. The mice are then assigned to either a control group and administered vehicle, or to a treatment group. Each group is then intraperitoneally administered an illustrative Purine Derivative (1.0 mg/kg). Both groups of animals are then monitored for a reaction for 30 minutes post-treatment to determine how much time each animal spends licking the treated paw. The licking time in control group (vehicle pretreated animals) is then compared to the licking time in the treatment group in order to calculate the analgesic effect. The 30 minute reaction period is divided into two phases: an early phase which lasts from 0 - 5 minutes post-treatment, and a late phase which lasts from 10 - 30 minutes post-treatment.
5.11 Example 11 Determination of the Effect of the Purine Derivatives on Pain
BALB/C mice (6-8 weeks of age) are intraperitoneally administered streptozotocin (40 mg/kg, once per day for 5 consecutive days) to induce diabetes (blood glucose levels are greater than 200 mg/mL). Three weeks after the first streptozotocin injection, the animals are intraperitoneally administered an •illustrative Purine Derivative (1 mg/kg) into a rear paw and post-treatment allodynia can be measured using an Electrovonfrey anesthesiometer (IITC Inc., Woodland Hills CA 91367). The analgesic activity of an illustrative Purine Derivative is measured at 0 minutes (control), 15 minutes, 30 minutes and 60 minutes time point after administration of an illustrative Purine Derivative.
5.12 Example 12 Determination of the Effect of the Purine Derivatives on Pain
Male Wistar rats (each weighing between 200- 250 g, kept under pathogen-free conditions at 24 — 250C and provided with standard rat chow and water ad libitum) are anaesthetized via intraperitoneal administration of pentobarbital (50 mg/kg) and placed in a stereotaxic frame. The atlanto-occipital membrane is exposed and a PE-10 catheter (7.5 cm) is inserted through an incision into the subarachnoidal space. The external end of the catheter is then fixed to the skull, the wound is closed, and the rats are allowed to recover for 7 days post- surgery. Animals without neurological deficits are placed in a plexiglass observation chamber on a metal mesh surface and mechanical thresholds of the plantar surface of the paw can be determined using a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) as follows: Following acclimation, the touch stimulator unit is placed under the animal's paw such that the filament is positioned under the target area of the paw. The filament is then lifted such that it contacted the pad of the animal's paw and continually exerted an increasing upward force on the paw until the animal withdrew the paw. The paw withdrawal threshold is measured 5 times in this manner in turns and the mean of the 5 values is calculated. After control threshold measurements are complete, carrageenan (3%, 100 μl) is administered subcutaneously into a hindpaw, resulting in marked swelling and redness of the treated paw. Three hours after the carrageenan administration, the threshold values are measured again. The animals are then divided into a control group (administered vehicle intrathecally) and a treatment group (adminstered an illustrative Purine Derivative intrathecally at in a 10 μl injection volume). Threshold determinations are repeated as described above at 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after the administration of vehicle or an illustrative Purine Derivative.
5.13 Example 13
Determination of the Effect of the Purine Derivatives on Pain
Male CD rats (each weighing from 220 g to 250 g) are prepared according to the procedure set forth in Z. Seltzer et al, Pain, 43:205 - 218 (1990). The rats are then anesthetized via intraperitoneal administration of sodium pentobarbital (50 mg/kg). A skin incision is made at the upper 1/3 and 2/3 left thigh area of each rat and the left sciatic nerve is exposed and freed from the surrounding connective tissue. An 8-0 nylon suture is then used to tightly ligate the left sciatic nerve of each rat so that the dorsal 1/3 to 1/2 of the nerve thickness is trapped in the ligature. The incision is closed using 4-0 sterile suture. Seven days post- surgery, the animals are put into four groups: a first group that is administered vehicle (control group); a second group that is administered an illustrative Purine Derivative at 0.1 mg/kg; a third group that is administered buprenorphine at 0.3 mg/kg; and a fourth group that is coadministered an illustrative Purine Derivative at 0.1 mg/kg and buprenorphine at 0.3 mg/kg. Animals in all four groups are assessed for allodynia immediately prior to treatment and at 10, 20, 30 and 60 minutes post-treatment using the Von Frey Hair test (G.M. Pitcher et al., J Neurosci Methods, 87:185-93 (1999)).
5.14 Example 14 Determination of the Effect of the Purine Derivatives on Heart Rate
Adult male Wistar rats (each weighing from about 350 g to about 400 g) are anesthetized as in Example 12, then prepared for monitoring of blood pressure and heart rate. Each animal's heart rate is measured, then an illustrative Purine Derivative is intravenously administered via the femoral vein at a dose of 1 ng/kg/minute, 10 ng/kg/minute, or 1000 ng/kg/minute (n = 2 animals per dosage size) for a total administration period of 20 minutes. Each animal's heart rate is then remeasured. The post-treatment heart rate is then compared to the pre-treatment heart rate.
5.15 Example 15 Determination of the Effect of the Purine Derivatives on Core Body Temperature
Two male Sprague-Dawley rats of about 400 g each were kept at 130C and slowly injected with 20 mg/mL of Compound I'-l dissolved in saline through a jugular venus (JV) catheter for about 2 minutes to reach a dose of 15 mg/kg. After the rats fell asleep, 20 mg/mL of Compound I'-l was continuously injected through the jugular venus catheter via a syringe pump for 4 hours at a rate 1 mL/h. The rats were then returned to their cages at room temperature. Their rectal temperature, respiratory rate, and behavior were recorded following 5 min, 10 min, 20 min, 30 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, and 4 h. Both animals survived the experiment. The results are shown in Table 3 A and Table 3B.
Table 3A
Parameters in the Determination of the Effect of the Purine Derivatives on Core Body
Temperature Up to 30 Minutes
Figure imgf000065_0001
Table 3B
Parameters in the Determination of the Effect of the Purine Derivatives on Core Body
Temperature After 30 Minutes
Figure imgf000066_0001
After the experiments, the animals were kept in the animal room and their behavior observed. The data set forth in Tables 3A and 3B indicate that Compound F-I, an illustrative Purine Derivative, reduces an animal's core body temperature.
5.16 Example 16
Determination of the Effect of the Purine Derivatives on Treatment or Prevention of
Glaucoma with Intraocular Hypertension
The effect of Compound I'-l on intraocular pressure (IOP) was examined in
New Zealand white rabbits. New Zealand white rabbits undergo a circadian change in intraocular pressure, such that lowest pressure values occur in the early morning and peak pressure values occur in the afternoon. This circadian rhythm is demonstrated in Figures 1-5 on the day before the study (i.e., t = -25 hours to t = 0 hours). Consistency of measurements is indicated by the fact the intraocular pressure at t=-23 hours and t=25 hours is essentially the same (see Figs. 1-5).
Compound I'-l was dissolved in saline, at concentrations 0.3, 1.0, 3.0, 10.0, and 30.0 mg/mL. One rabbit was administered with each each dose level. One drop (about 100 μL) of the saline solution of Compound I'-l was applied to the external surface of one eye of each rabbit. Compound I'-l was administered at t=0 hours, 3 hours after the animal house dark period ended (lights came on in the rabbit house at t=-3 hours). Thus, Compound I'-l was administered when the level of intraocular pressure was low relative to other timepoints during the day and night. After administration with Compound I'-l, the intraocular pressure did not increase to the normal day values (see Figs. 1-5). For all administered concentrations of
Compound I'-l, the lowest intraocular pressure values were in the range of 3 to 4 mmHg, at a timepoint that a New Zeland white rabbit would be expected to have intraocular pressure values of 11 to 13 mmHg. Thus, treatment with Compound I'-l resulted in a reduction of intraocular pressure values by 8 to 10 mmHg, relative to expected values. Duration of the effect of Compound I'-l varied according to the magnitude of the dose. Recovery of intraocular pressure values to normal levels occurred at about t=6 hours, when the administered concentration of Compound I'-l was 0.3 mg/mL (Fig. 1), and beyond t=7 hours, when the administered concentration of Compound I'-l was 30 mg/mL (Fig. 5). No eye irritation was observed in any animal. The data set forth in Figs. 1-5 indicate that Compound I'-l, an illustrative Purine
Derivative, reduces an animal's intraocular pressure and, accordingly, is useful for treating or preventing glaucoma with intraocular hypertension.
The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention.
Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. All references cited herein are incorporated by reference in their entirety.

Claims

What is claimed is:
1. A compound having the formula
Figure imgf000068_0001
(D or a pharmaceutically acceptable salt thereof, wherein
A iS -CH2OH; B and C are -OH; D is
Figure imgf000068_0002
A and B are trans with respect to each other; B and C are cis with respect to each other;
C and D are cis or trans with respect to each other;
R1 is -H, -halo, -CN, -N(R2)2, -OR2, -SR2, -NHC(O)R2, -NHC(O)N(R2)2, -NHC(O)OR2, -C(O)OR2, -C(O)R2, -C(O)N(R2)2, -OC(O)N(R2)2, -C(halo)3, or -NO2; each R2 is independently -H, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(CH2)n-aryl, -(CH2)n-(3- to 7-membered monocyclic heterocycle), -(CH2)n-(8- to 12-membered bicyclic heterocycle), -(CH2)H-(C3-C8 monocyclic cycloalkyl), -(CH2)n-(C3-C8 monocyclic cycloalkenyl), -(CH2)n-(C8-C12 bicyclic cycloalkyl), or -(CH2)n-(C8-C12 bicyclic cycloalkenyl); each n is an integer ranging from O to 6; each p is an integer ranging from 1 to 6; and each q is an integer ranging from 1 to 6.
2. The compound of claim 1 , wherein q is 3.
3. The compound of claim 1 , wherein q is 4.
4. The compound of claim 1 , wherein p is 1.
5. The compound of claim 2, wherein p is 1.
6. The compound of claim 3, wherein p is 1.
7. The compound of claim 1 , wherein R1 is -H.
8. The compound of claim 1, wherein R1 is -halo.
9. The compound of claim 9, wherein R1 is -Cl.
10. The compound of claim 2, wherein p is 1 and R1 is — H.
11. The compound of claim 2, wherein p is 1 and R1 is -Cl.
12. The compound of claim 3, wherein p is 1 and R1 is — H.
13. The compound of claim 3, wherein p is 1 and R1 is -Cl.
14. The compound of claim 1 having the structure:
Figure imgf000069_0001
(Ia') or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 having the structure:
Figure imgf000070_0001
or a pharmaceutically acceptable salt thereof.
16. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt of the compound of claim 1 and a physiologically acceptable carrier or vehicle.
17. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt of the compound of claim 14 and a physiologically acceptable carrier or vehicle.
18. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt of the compound of claim 15 and a physiologically acceptable carrier or vehicle.
19. A method for treating a neurological disorder, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
20. A method for treating an ophthalmic condition, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
21. A method for treating a cardiovascular disease, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
22. A method for treating an ischemic condition, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
23. A method for treating diabetes, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
24. A composition comprising a cardioplegia-inducing agent, an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1, and a physiologically acceptable carrier or vehicle.
25. A method for protecting an animal's heart against myocardial damage during cardioplegia, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
26. A method for reducing an animal's core body temperature, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
27. A method for reducing an animal' s rate of oxygen consumption, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
28. A method for treating obesity, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
29. A method for treating or preventing a wasting disease, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
30. A method for treating or preventing a reperfusion injury, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
31. The method of claim 30, wherein the reperfusion injury results from cardiopulmonary bypass surgery.
32. A method for treating a tachycardia, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
33. The method of claim 32, wherein the tachycardia is atrial fibrillation or a supraventricular tachycardia.
34. The method of claim 32, wherein the treating includes lowering the animal's cardiac ventricular rate to a rate of from about 60 beats per minute to about 100 beats per minute.
35. The method of claim 32, wherein the treating includes lowering the animal's cardiac ventricular rate to a rate of from about 100 beats per minute to about 140 beats per minute.
36. The method of claim 32, wherein the treating includes lowering the animal's cardiac ventricular rate to a rate of not less than about 40 beats per minute.
37. A method for converting a cardiac arrhythmia to a noπnal sinus rhythm, the method comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
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