MX2008006793A - Purine derivatives and methods of use thereof - Google Patents

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 Requests This Application claims the benefit of the Request Provisional North American No. 60 / 740,795, filed November 30, 2005, which is incorporated in its entirety to the present invention as a reference. Field of the Invention The present invention relates to Purine Derivatives; compositions comprising an effective amount of a Purine Derivative; and methods for reducing the core temperature of the animal's body, protecting the animal's heart against damage to the myocardium during cardioplegia; or to treat or prevent a cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, an impact injury, obesity, a wasting disease, or diabetes, wherein the methods comprise administering an effective amount of a Purine Derivative to an animal that needs it. Background of the Invention Adenosine is a naturally occurring purine nucleoside, which is ubiquitous in mammalian cell types. Adenosine exerts its biological effects by interacting with cell surface receptors A ^ A2 (sub-classified additionally as A2A and A2B) and A3 that modulate important physiological processes. The Ai and A2A receptor subtypes are considered to play complementary roles in adenosine regulation of a cell's energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and activates locally the Ai receptor to decrease the oxygen demand or activate the A2A receptor to increase the oxygen supply, reinstalling the balance of supply and demand of energy within the tissue. The combined action of the subtypes of A ^ and A2 increases the amount of oxygen available to the tissue and protects cells against damage caused by a short-term oxygen imbalance. One of the important functions of indigenous adenosine is to avoid tissue damage during traumas such as hypoxia, an ischemic condition, hypotension and seizure activity. In addition, the modulation of the Ai receptors decreases the conduction velocity in the atrioventricular node of the heart, resulting in the normalization of supraventricular tachycardia and the control of the cardiac ventricular range during atrial fibrillation and agitation. Modulation of A2A receptors also regulates coronary vasodilation. Adenosine is also a neuromodulator, which modulates the molecular mechanisms that underlie many aspects of the physiological function of the brain, transmitting central inhibitory effects. An increase in the release of neurotransmitters follows traumas such as hypoxia, ischemia and attacks. Neurotransmitters are ultimately responsible for neural degeneration and neural death, which can cause brain damage or death. Adenosine is considered to be an endogenous anti-seizure agent that inhibits the release of glutamate from neurons of excitation and neuronal suspension. The adenosine agonists, therefore, are useful as anti-epileptic agents. Adenosine plays an important role as a cardioprotective agent. Endogenous adenosine levels increase in response to ischemia and hypoxia and protect cardiac tissue during and after trauma (preconditioning). In this way adenosine agonists are useful as cardioprotective agents. The preparation and use of a number of Ai receptor agonists have been described in previous publications (Moos et al., J. Med. Chem. 28: 1383-1384 (1985), Thompson et al., J. Med. Chem. 34: 3388-3390 (1991), Vittori and associates, J. Med. Chem. 43: 250-260 (2000), Roelen and associates, J Med. Chem, 39; 1463-1471 (1996), van der Wenden and associates, 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); North American No. 5,589,467 of Lau and associates; No. 5,789,416, from Lum and associates; and CE Publication. Muller, Current Medicinal Chemistry 2000, 7, 1269-1288). The mention of any reference in Section 2 of the present application is not an admission that the reference is a prior art to the present application. Brief Description of the Invention In one embodiment, the present invention provides compounds having the Formula (I ): and pharmaceutically acceptable salts thereof, wherein A is -CH 2 OH; B and C are -OH; D is: A and B are trans with respect to one another; B and C are cis with respect to one another; C and D are cis or trans with respect to one another; 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, NO; each R 'is independently -H, alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, - (CH2) n-aryl, - (CH2) n- (monocyclic heterocyclic 3-7 membered), - (CH2) n- (bicyclic heterocycle of 8 a 12 members), - (CH2) n- (C3-C8 monocyclic cycloalkyl), - (CH2) n- (C3-C8 monocyclic cycloalkenyl), - (CH2) H- (C8-C? 2 bicyclic cycloalkyl), or - (CH2) n- (Bicyclic cycloalkenyl C8-C? 2); each n is an integer that fluctuates from 0 to 6; each p is an integer that fluctuates 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 cardiovascular disease, a neurological disorder, an ophthalmic condition, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes (each being "Condition"); (ii) reducing the core temperature of an animal's body; or (iií) protect the heart of an animal against damage to the myocardium during cardioplegia. The present invention also provides compositions comprising an effective amount of a Derivative of Purine and a physiologically acceptable carrier or vehicle. The compositions are useful for: (i) treating or preventing a Condition; (I) reduce the core temperature of an animal's body; or (ii) protect the heart of an animal against damage to the myocardium during cardioplegia. The present invention further provides methods for: (i) treating or preventing a Condition; (ii) reducing the core temperature of an animal's body; or (iii) protecting the heart of an animal against damage to the myocardium during cardioplegia, wherein the methods comprise administering an effective amount of a Purine Derivative to an animal in need thereof. Brief Description of the Drawings Figure 1 illustrates infra-ocular pressure measured in an adult New Zealand White rabbit, before (from -25 hours to 0 hours) and after treatment (up to 25 hours after treatment) with 100 μl of 0.3 mg / ml of Compound r-1; Figure 2 illustrates the intraocular pressure measured in an adult New Zealand White rabbit, before (from -25 hours to 0 hours) and after treatment (up to 25 hours after treatment) with 100 μl of 1.0 mg / ml of Compound r-1; Figure 3 illustrates the intraocular pressure measured in an adult New Zealand White rabbit, before (from -25 hours to O hours) and after treatment (up to 25 hours after treatment) with 100 μl of 3.0 mg / ml of Compound r-1; Figure 4 illustrates intraocular pressure measured in an adult New Zealand White rabbit, before (from -25 hours to 0 hours) and after treatment (up to 25 hours after treatment) with 100 μl of 10 mg / ml of Compound r-1; and Figure 5 illustrates intraocular pressure measured in an adult New Zealand White rabbit, before (from -25 hours to 0 hours) and after treatment (up to 25 hours after treatment) with 100 μl of 30 mg / ml of the Compound r-1. Detailed Description of the Invention Definitions The term "C 1 -C 1 or alkyl" as used in the present invention 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 methylethyl, propyl, isopropyl, butyl, sec-butyl, fer-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, iso-octyl, neo-octyl, nonyl, isononyl, neononyl , decilo, sodecilo and neodecile. In one embodiment, the d-C10 alkyl group is substituted with one or more of the following groups: - groups halo, -O- (C? -C6 alkyl), -OH, -CN, -COOR ', -OC (O) R \ -N (R') 2, -NHC (O) R 'or -C (O ) NHR 'wherein each R' is independently -H or -C? -C6 unsubstituted alkyl. Unless indicated, the C -? - C10 alkyl is unsubstituted. The term "C? -C6 alkyl" as used in the present invention refers to a straight or branched chain saturated hydrocarbon having from 1 to 6 carbon atoms. Representative CrC6 alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, re-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. The term "C2-C6 alkenyl" refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbon atoms and at least one double bond. Representative C2-C6 alkenyl groups include, but are not limited to, ethylene, propylene, 1-butylene, 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, -O-id -C-alkyl groups), -OH, -CN, -COOR ', -OC (O) R groups \ -N (R ') 2, -NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or -CrC6 unsubstituted alkyl. Unless indicated, the C2-C6 alkenyl group is unsubstituted. The term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbon atoms. carbon and at least one triple bond. Representative C2-C6 alkynyl groups include, but are not limited to, acetylene, propine, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentine, 1-hexyne, 2-hexyne , 3-hexyne and isohexino. In one embodiment, the C2-C6 alkynyl group is substituted with one or more of the following groups: -halo, -O- (C? -C alkyl), -OH, -CN, -COOR ', -OC groups. O) R ', -N (R') 2, -NHC (O) R 'or -C (O) NHR' wherein each R 'is independently -H or -C? -C6 unsubstituted alkyl. Unless indicated, the C2-C6 alkynyl group is unsubstituted. The term "aryl" as used in the present invention refers to a phenyl group or a naphthyl group. In one embodiment, the aryl group substituted with one or more of the following groups: -halo, -0- (CrC6 alkyl), -OH, -CN, -COOR ', -OC (O) R \ -N (R ') 2, -NHC (O) R' or -C (0) NHR 'wherein each R' is independently -H or -d-Cβ unsubstituted alkyl. Unless indicated, the aryl is unsubstituted. The term "C3-C8 monocyclic cycloalkyl" as used in the present invention is a saturated non-aromatic monocyclic cycloalkyl ring of 3-, 4-, 5-, 6-, 7- or 8-members. 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, -O- (C1-C6 alkyl), -OH, -CN, -COOR ', -OC (O) R \ -N (R') 2, -NHC (O) R 'or -C (O) NHR 'wherein each R' is independently -H or -d-Cβ unsubstituted alkyl. Unless indicated, the C3-C8 monocyclic cycloalkyl is unsubstituted. The term "C3-C8 monocyclic cycloalkenyl" as used in the present invention is a non-aromatic monocyclic carbocyclic ring of a 3-, 4-, 5-, 6-, 7- or 8-member having at least one bond double endocyclic, but it is not aromatic. It will be understood that when the 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 adhere 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, cyclo-octenyl, 1,3-cyclo-octadienyl, 1,4-cyclo-octadienyl, -1, 3,5-cyclo-octatrienyl. In one embodiment, the C3-C8 monocyclic cycloalkenyl group is substituted with one or more of the following groups: -halo, -O- (C1-C6 alkyl), -OH, -CN, -COOR ', -OC (O) groups ) R \ -N (R ') 2, - NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or -d-C6 unsubstituted alkyl. Unless otherwise indicated, cycloalkenyl monocyclic C3-C8 is unsubstituted. The term "C 8 -C 2 bicyclic cycloalkyl" as used in the present invention is a non-aromatic bicyclic cycloalkyl ring system, saturated with 8-, 9-, 10-, 11- or 12-member. Representative C8-C? 2 bicyclic cycloalkyl groups include, but are not limited to, decahydronaft aleno, octahydro-indene, decahydrobenzocycloheptene, and dodecahydroheptalene. In one embodiment, the bicyclic cycloalkyl group C8-d2 is substituted with one or more of the following groups: -halo, -O- (C1-C6 alkyl), -OH, -CN, -COOR ', -OC (O) groups ) R \ -N (R ') 2, - NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or -Ci-C6 unsubstituted alkyl. Unless indicated, the bicyclic cycloalkyl C8-C- | 2 is unsubstituted. The term "bicyclic cycloalkenyl C8-C-? 2" as used in the present invention is a non-aromatic bicyclic cycloalkyl ring system of 8-, 9-, 10-, 11- or 12-member, which has the minus an endocyclic double bond. It will be understood that when either of two groups, together with the carbon atom to which they adhere, form a C 8 -C 2 bicyclic cycloalkenyl group, the carbon atom to which the two groups adhere remains tetravalent. Representative C8-C12 bicyclic cycloalkenyl groups include, but are not limited to, octahydronaphthalene, hexahydronaphthalene, hexahydroindene, tetrahydroindene, octahydrobenzocycloheptene, hexahydrobenzocycloheptene, tetrahydrobenzocycloheptene, decahydroheptalene, octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene. In one embodiment, the C 8 -C 2 β-cycloalkyl bicyclic group is substituted with one or more of the following groups: -halo, -O- (C 1 -C 6 alkyl), -OH, -CN, -COOR ', -OC groups (O) R \ -N (R ') 2, -NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or -d-C6 unsubstituted alkyl. Unless indicated, the bicyclic cycloalkenyl C8-C12 is unsubstituted. The term "effective amount" as used in the present invention refers to an amount of a Purine Derivative that is effective to: (i) treat or prevent a Condition; (ii) reducing the core temperature of an animal's body; or (iii) protect the heart of an animal against damage to the myocardium during cardioplegia. The term "halo" as used in the present invention refers to -F, -Cl, -Br or -I. The term "3- to 7-membered monocyclic heterocycle" refers to: (i) a non-aromatic 3- or 4-membered monocyclic cycloalkyl wherein 1 of the ring carbon atoms has been replaced with an N, O or S; or (ii) an aromatic or non-aromatic monocyclic cycloalkyl of 5-, 6-, or 7- in which 1 to 4 of the ring carbon atoms have been independently replaced with an N, O or S atom. The heterocycles monocyclics from 3 to 7 non-aromatic members they can adhere through a nitrogen atom, sulfur, or ring carbon. Monocyclic heterocycles of 3 to 7 aromatic members are adhered through a ring carbon atom. Representative examples of a 3 to 7 membered monocyclic heterocycle 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, piridooxazole, piridoimidazole, piridotiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, tri azole, In one embodiment, the 3- to 7-membered monocyclic heterocycle group is substituted with one or more of the following groups: -halo, -O- (C1-C6 alkyl), -OH groups , -CN, -COOR ', -OC (O) R \ -N (R') 2, -NHC (O) R 'or -C (0) NHR' wherein each R "is independently -H or -d -C6 unsubstituted alkyl Unless otherwise indicated, the 3- to 7-membered monocyclic heterocycle is unsubstituted. The term "8 to 12 membered bicyclic heterocycle" refers to an aromatic or non-aromatic bicyclic cycloalkyl of 8 to 12 members in which one or both of the rings of the bicyclic ring system has from 1 to 4 of its ring atoms. ring carbon independently replaced with an 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 adhered through a nitrogen, sulfur, or ring carbon atom. A monocyclic heterocycle of 8 to 12 aromatic members is adhered through 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, benztetrolyl, benzisoxazolyl, benzisothiazole, benzimidazolinyl, cinnolinyl, decahydroquinolinyl, 1H-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 be substituted with one or more of the following groups: halo groups, -O- (C1-C6 alkyl), -OH, -CN, -COOR ' , - OC (O) R \ -N (R ') 2. -NHC (O) R 'or -C (O) NHR "wherein each R' is independently -H or -d-C6 unsubstituted alkyl, unless otherwise indicated, the 8 to 12 membered bicyclic heterocycle is unsubstituted .

The phrase "pharmaceutically acceptable salt", as used in the present invention, is a salt of an acid or base 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, salt ICI lato, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate , fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (for example 1, 1 '-met? leno-b? s- (2-h? drox? -3-naphthoate)) The pharmaceutically acceptable salt can also be a camphor sulfonate 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 The base Suitable materials include, but are not limited to, alkali metal hydroxides such as sodium, potassium, and lithium, alkaline earth metal hydroxides such as calcium and magnesium, hydroxides of other metals, such as aluminum and zinc, ammonia, and amines. organic, such as unsubstituted or hydroxy substituted mono- or tpalkylamines, dicyclohexylamine, tpbu ti I or amine, pipdine, N-methyl, N-ethylamma, diethylamine, tetylamine, mono-, bis-, or tr? s- (2 Lower -OH-alkylamines), such as mono-, bis-, or tr? S- (2- hydroxyethyl) amine, 2-hydroxy-re-butylamine, or tri s- (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, for example, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee or bamboo. In one modality, a monkey is a rhesus. In another modality, an animal is a human. The term "isolated and purified" as used in the present invention means separate from other components of a reaction mixture or natural source. In certain embodiments, the isolate comprises 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 in the present invention, means that a Purine Derivative contains no more 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 yet 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 other corresponding anomer" as used in the present invention 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 other corresponding anomer contains no more than about 5% by weight of its other corresponding anomer. In a further embodiment, a Purine Derivative that is substantially free of its other corresponding 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 other corresponding anomer contains no more than about 0.5% by weight of its corresponding other anomer. In yet 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 in the present invention are illustrated using bold or dotted lines to represent chemical bonds. These bold or dotted lines illustrate absolute stereochemistry. A bold line indicates that a substituent is above the plane of the carbon atom to which it adheres and a dotted line indicates that a substituent is below the plane of the carbon atom to which it adheres. For example, in the illustration that follows: group A is above the plane of the carbon atom to which it adhere and group B is below the plane of the carbon atom to which it adheres. It will be understood that in Group D of the Derivatives of Purine of the Formula (I), which are illustrated below: the - (CH2) POH group can be attached to any carbon atom of the group to which it adheres. The abbreviations which follow in the present invention are used 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 a 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 PURINE DERIVATIVES 4.2.1 PURINE DERIVATIVES OF FORMULA (I) As stated above, the present invention comprises Purine Derivative having Formula (I): where A, B, C and D were previously defined for the Purine derivatives of the formula (I), and A and B are trans with respect to one another; 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 modality, R is -halo. In a specific embodiment, R1 is -Cl. In another embodiment, R1 is -CN. Still in another modality, R is -N (R) 2. Still in another modality, R1 is -OR2. In a further embodiment, R1 is -SR2. In another embodiment, R1 is -NHC (O) OR2, -NHC (O) R2, or -NHC (0) N (R2) 2. In another embodiment, R1 is -C (0) OR2, -C (0) R2, -C (0) N (R2) 2, or - OC (0) N (R2) 2. Still in another embodiment, R1 is CF3.

Still in another modality, R1 is -N02. In one modality, p is 1. In another modality, p is different from 1. In one modality, q is 1. In another modality, q is 2. Even in another modality, q is 3. Still in another modality, q is 4. Still in another modality, q is 3 or 4. In a further modality, q is 5. In another modality, q is 6. In one modality, R1 is -H, p is 1 and q is 1. In another modality, R1 is -halo, p is 1 and q is 1. Still in another modality, R1 is -Cl, p is 1 and q is 1. Still in another modality, R1 is -H or -halo and q is 3 or 4. Still in another modality, R1 is -H or -halo, q is 3 or 4 and p is 1. Still in 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 one another. In another modality, C and D are trans with respect to one another. 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 present invention further provides Purine Derivatives of the Formula (I) which are in isolated and purified form. The present invention further provides methods for treating or preventing a Condition, wherein the methods comprise administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof.

The present invention further provides methods for reducing the core temperature of an animal body, wherein the methods comprise administering an effective amount of a Purine Derivative of Formula (I) to an animal in need thereof. The present invention further provides methods for protecting the heart of an animal against damage to the myocardium during cardioplegia, wherein the method comprises 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, which are illustrated either by Formula (la ') or Formula (la "): (the') wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I). A Purine Derivative of the Formula (la ') is the corresponding opposite enantiomer of a Purine Derivative of the Formula (the ") when the group A of the Purine Derivative of the Formula (la1) is the same as the group A of the Formula Purine Derivative of the Formula (the ") and when the group D of the Purine Derivative of the Formula (the ') is the same as the group D of the Purine Derivative of the Formula (the"). Formula (")" is the corresponding opposite enantiomer of a Purine Derivative of the Formula (la1) when group A of the Purine Derivative of the Formula (")" is the same as group A of the Purine Derivative of the Formula (la1) and when the group D of the Purine Derivative of the Formula (the ") is the same as the group D of the Purine Derivative of the Formula (la '). In one embodiment, the Purine Derivatives of Formula (I) have the formula (la '), illustrated above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and where the Purina Derivatives of the Formula (') are substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of Formula (I) have the formula (""), illustrated above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of the Formula (the ") are substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (') and a Purine Derivative of the Formula (the ") wherein the amount of the Purine Derivative of the Formula (la') exceeds the amount of the Purine Derivative of the Formula (the"). In a further embodiment, the Purine Derivatives of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (la ') and a Purine Derivative of the Formula (the ") wherein the amount of the Derivative of Purine of the Formula (the ") exceeds the amount of the Purine Derivative of the Formula (la '). In another modality, the Purine Derivatives of Formula (I) exist as a racemic mixture of a Purine Derivative of Formula (la1) and a Purine Derivative of Formula (")." In another embodiment, the Purine Derivatives of the Formula (I) may exist in the form of a single enantiomer, for example, which is illustrated by the formulas (laa ') or (laa "): (Iaa ') (Iaa ") wherein A, B, C and D are defined above for the Purine Derivatives of the Formula (I) A Purine Derivative of the Formula (laa ') is the corresponding opposite enantiomer of a Purine Derivative of Formula (laa ") when a group A of a Purine Derivative of the Formula (laa ') is the same as group A of the Purine Derivative of the Formula (laa") and when a group D of the Purine Derivative of Formula (laa ') is the same as group D of the Purine Derivative of the Formula (laa "). A Purine Derivative of the Formula (laa ") is the corresponding opposite enantiomer of a Purine Derivative of the Formula (laa1) when a group A of the Purine Derivative of the Formula (laa") is the same as the group A of the Formula Purine Derivative of the Formula (laa ') and when the group D of the Purine Derivative of the Formula (laa ") is the same as the group D of the Purine Derivative of the Formula (laa').

In one embodiment, the Purine Derivatives of Formula (I) have the formula (laa '), illustrated above, wherein A, B, C and D were defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of the Formula (laa ') are substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of Formula (I) have the formula (laa "), illustrated above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of the Formula (laa ") are substantially free of their corresponding opposite enantiomers. In another modality, the Purine Derivatives of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (laa1) and a Purine Derivative of the Formula (laa ") wherein the amount of the Purine Derivative of the Formula (laa ') exceeds the amount of the Derivative of Purine of the Formula (laa ").

In a further embodiment, the Purine Derivatives of Formula (I) exist as a mixture of the Purine Derivative of the Formula (laa ') and a Purine Derivative of the Formula (laa "), wherein the amount of the Derivative of Purine of the Formula (laa ") exceeds the amount of the Purine Derivative of the Formula (laa '). In another embodiment, the Purine Derivatives of the Formula (I) exist as a racemic mixture of a Purine Derivative of the Formula (laa ') and a Purine Derivative of the Formula (laa.) A Purine Derivative of the Formula (laa') is the other corresponding anomer of a Purine Derivative of the Formula (the ') when the Group A of the Purine Derivative of the Formula (laa ') is the same as group A of the Purine Derivative of the Formula (la') and when the group D of the Purine Derivative of the Formula (laa ') is the same that the group D of the Purine Derivative of the Formula (la '). A Purine Derivative of the Formula (la') is the other corresponding anomer of the Purine Derivative of the Formula (laa ') when the group A of the Derivative of Purine of the Formula (la ') is the same as group A of the Purine Derivative of the Formula (laa') and when the group D of the Purine Derivative of the Formula (la ') is the same as the group D of the Formula Purine Derivative of the Formula (laa ') A Purine Derivative of the Formula (laa ") is the other corresponding anomer of a Purine Derivative of the Formula (the") when the Group A of the Purine Derivative of the Formula (laa ") is the same as group A of the Purine Derivative of the Formula (the") and when the group D of the Purine Derivative of the Formula (laa ") is the same that the group D of the Purine Derivative of the Formula (the "). A Purine Derivative of the Formula (the ") is the other corresponding anomer of a Purine Derivative of the Formula (laa ") when the group A of the Purine Derivative of the Formula (the") is the same as the group A of the Purine Derivative of the Formula (laa ") and when the group D of the Purine Derivative of the Formula (the ") is the same as group D of the Purine Derivative of the Formula (laa")., the Purine Derivatives of Formula (I) have the formula (laa '), illustrated above, wherein A, B, C and D were defined above for the Purine Derivatives of Formula (I), and where the Purine Derivatives of the Formula (laa ') are substantially free of their other corresponding anomer. In another embodiment, the Purine Derivatives of Formula (I) have the formula (laa "), illustrated above, wherein A, B, C and D were defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of the Formula (laa ") are substantially free of their other corresponding anomer. In one embodiment, the Purine Derivatives of Formula (I) have the formula (la '), illustrated above, wherein A, B, C and D were defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of the Formula (') are substantially free of their corresponding other anomer. In another embodiment, the 'Purine Derivatives of Formula (I) have the formula (the "), illustrated above, wherein A, B, C and D were defined above for the Purine Derivatives of Formula (I), and wherein the Purine Derivatives of the Formula (") are substantially free of their corresponding other anomer. Purine of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (la ') and a Purine Derivative of the Formula (laa') wherein the amount of the Purine Derivative of the Formula (la ') exceeds the amount of the Derivative of Purine of the Formula (laa '). In another modality, the Purine Derivatives of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (la ') and a Purine Derivative of the Formula (laa') wherein the amount of the Purine Derivative of the Formula (laa ') exceeds the amount of the Derivative of Purine of the Formula (la '). In a further embodiment, the Purine Derivatives of the Formula (I) exist as an equal mixture of a Purine Derivative of the Formula (la ') and a Purine Derivative of the Formula (laa'). In one embodiment, the Purine Derivatives of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (")" and a Purine Derivative of the Formula ("la") wherein the amount of the Purine Derivative of the Formula (")" exceeds the amount of the Purine Derivative of the Formula ("la").

In another embodiment, the Purine Derivatives of the Formula (I) exist as a mixture of a Purine Derivative of the Formula (")" and a Purine Derivative of the Formula ("la") wherein the amount of the Purine Derivative of the Formula (laa ") exceeds the amount of the Purine Derivative of the Formula ("). In a further embodiment, the Purine Derivatives of Formula (I) exist as an equal mixture of a Purine Derivative of the Formula (")" and a Purine Derivative of the Formula ("la"). Illustrative Purine Derivatives of Formula (I) include the compounds of formula (I ') as set forth below: d ') or a pharmaceutically acceptable salt thereof. 4.3 METHODS FOR PREPARING PURINE DERIVATIVES Purine derivatives can be made using synthetic procedures described below in Schemes 1 to 5. Scheme 1 shows methods for making specific stereoisomeric 6-chloroadenosine intermediates that are useful for making the Derivatives from Purine of the Formula (I) Scheme 1 4 wherein R1 is as defined above for the Purine Derivatives of the Formula (I). The compound of Formula 1 can be coupled with a compound of Formula 2 using lithium hexamethyldisilazide and trimethylsilyl triflate, followed by removal of acetonide using trifiuoroacetic acid to provide 6-chloroadenosine intermediates of Formula 3 and its other corresponding anomers of the Formula 4. Similarly, the compound of Formula 5 can be coupled with a compound of Formula 2 using lithium hexamethyldisilazide and tri-methyl triflate, followed by acetonide elimination using trifiuoroacetic acid to provide compounds of the Formula 6 and its other corresponding anomers of Formula 7. The useful methodology for making the Purine Derivatives of Formula (I) are described in Scheme 2a. Esq uema 2a 8a Purine Derivatives of Formula (I) wherein R 1, p and q are as defined above for the Purine Derivatives of Formula (I). A compound of the formula 8a is reacted with a compound of the formula 9a in refluxing ethanol to provide the Purine Derivatives of the Formula (I). The useful methodology for making the Purine Derivatives of Formula (I ') is described in Scheme 2b. Scheme 2b 8b Purine Derivatives of the Formula (I ') wherein R1, p and q are as defined above for the Purine Derivatives of Formula (I '). A compound of the formula 8b is reacted with a compound of the formula 9a in refluxing ethanol to provide the Purine Derivatives of the Formula (I '). A variety of compounds 9a, including particular stereoisomers, are commercially available from Acros Organics (Geel, Belgium), AFID Therapeutics Inc. (Lansing, Ml), and Sigma-Aldrich (St. Louis, MO). In some embodiments, R1 is -H or -Cl. Scheme 3 establishes the useful methodology for making the compounds of formula 9, wherein p is 1 and q is as defined above for the Purine Derivatives of Formula (I).

Esq uema 3 Amine Intermediates of Formula 9 where p is 1 wherein R 'is -H or methyl, p is 1 and q is as 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 resulting 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. Compounds of formula 10 are commercially available, or alternatively, they can be prepared from commercially available starting materials using methods known to those skilled in the art. Organic synthesis. For example, the substituted keto-esters-1, 2 of formula 10 can be synthesized by reacting a cycloalkanone enolate (prepared from commercially available cycloalkanone) with alkyl chloroformate; substituted keto-esters-1, 3 of formula 10 can be synthesized through 1,4 addition to a commercially available conjugated cycloalkenone; and substituted keto-esters-1, 4 of formula 10 can be synthesized through oxidation of cycloalkanols substituted with 4-carboxylate commercially available. Scheme 4 establishes the useful methodology for making the compounds of formula 9, wherein p is an integer ranging from 3 to 6 and q is as defined above for the Purine Derivatives of Formula (I). Scheme 4 H2- (CH2) rC (0) OCH3 reduction (CH2) pOH H2N 'H Amine intermediates of the formula 9 wherein p is 3-6, wherein R 'is -H or methyl, p is an integer ranging from 3 to 6, q was defined above for the Purine Derivatives of Formula (I), and r is an integer ranging from 0 to 3. It is reacting a compound of formula 10 with hydroxylamine, and the resulting 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 through a Wittig reaction to provide a composed of formula 13 (see March Publication, Advanced Organic Chemistry Reactions, Mechanisms, and Structure, 956-963 (4th edition 1992)) Hydrogenation of the compound of formula 13, using for example H2 and Pd / C, provides the compound of formula 14, which can subsequently be reduced using, for example, lithium aluminum hydride to provide compounds of formula 9, wherein p is an integer ranging from 3 to 6 and q was defined above for The Purine Derivatives of Formula (I) Scheme 5 establishes useful methodology for making the amine intermediates of formula 9, wherein p is 2 and q was defined above for the Purine Derivatives of Formula (I) Scheme 5 Amine Intermediates of formula 9 where p is 2, wherein p is an integer that ranges from 3 to 6 and q was 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 resulting oxime, using, for example, magnesium in the presence of Ammonium format (see Abiraj and Associates Publication, Synth Commun. 34: 599-605 (2004)). Subsequently, a methylene group is inserted between the ethyl ester group and the carbocyclic ring of 15 using, for example, a Kowalski ester homologation reaction (Kowalski et al., J. Am. Chem. Soc. 57: 7194 (1992)) to provide a compound of formula 16. The compound of formula 16 can subsequently 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 was 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 those skilled in the art of organic synthesis. 4.4 THERAPEUTIC / PROFILACTIC ADMINISTRATION AND COMPOSITIONS OF THE PRESENT INVENTION Due to their activity, Purine Derivatives are conveniently useful in veterinary and human medicine. As described above, Purine Derivatives are useful for: (i) treating or preventing a Condition in an animal that needs it; (I) reduce the core temperature of the animal's body; or (iii) protect the heart of an animal against damage to the myocardium during cardioplegia.

When administering an animal, the Purine Derivatives can be administered as a compound and a composition comprising a physiologically acceptable carrier or vehicle. The compositions of the present invention, which comprise a Purine Derivative, can be administered orally. Purine Derivatives can also be administered through any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous lining (e.g., oral, rectal, or intestinal mucosa) and can be administer together with another biologically active agent. The administration can be systemic or local. Various delivery systems can be used, including encapsulation in liposomes, microparticles, microcapsules and capsules. 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 cases, the administration will result in the release of purine derivatives in the bloodstream. The mode of administration can be left to the specialist's judgment. In one embodiment, 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 the core temperature of the animal's body, the Purine Derivatives can be administered by continuous intravenous infusion. In other embodiments, it may be desirable to locally administer the Purine Derivatives. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, for example, together with a bandage after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, the implant being a porous, non-porous or gelatinous material, including membranes, such as elastic membranes or fibers. In yet another embodiment, it may be desirable to administer the Purine Derivatives in an ocular form. The ocular administration of the Purine Derivatives can be achieved using eye drops or contact lenses coated or impregnated with the Purine Derivative. In certain modalities, it may be desirable to introduce the Purine derivatives in the central nervous system, circulatory system or gastrointestinal tract through any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema or injection adjacent to a peripheral nerve Transventicular injection can be facilitated through a ventricular catheter, for example, due to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, for example, through the use of an inhaler or nebuhzador, and the formulation with an aerosolization agent, or through perfusion in a fluorocarbon or synthetic pulmonary surfactant In certain embodiments, the Purine Derivatives can be formulated as a suppository, with traditional linkers and carriers or vehicles, such as tpglicépdos In another embodiment, the Purine Derivatives can be delivered in the form of a vesicle, in particular a liposome (see Langer Publication, Science 249 1527-1533 (1990) and Lopez-Berestem and Associates, Liposomes m the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)) Still in another embodiment, Purine Derivatives can be supplied in a system of controlled release or sustained release system (for example, see Goodson's publication, in Medical Applications of Controlled Relay, supra, vol 2, pp 115-138 (1984)) Other controlled or sustained release systems described in the Langer Publication , Science 249 1527-1533 (1990) can be used In one embodiment, a pump can be used (Langer, Science 249 1527-1533 (1990), Sefton, CRC Cpt Ref Biomed Eng 1_4: 201 (1987); Buchwald et al., Surgery 88.:507 (1980); and Saudek and associates, N. Engl. J Med. 321: 574 (1989)). In another modality, polymeric materials can be used (see the Publications of Medical Applications of Controlled Relay (Langer and Wise eds., 1974), Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Peppas, J Macromol, Sci. Rev. Macromol, Chem. 2_: 61 (1983), Levy and Associates, Science 228: 190 (1935), During and Associates, Ann. Neural 25_: 351 (1989), and Howard and Associates , J. Neurosurg, 71: 105 (1989)). In yet another embodiment, a controlled or sustained release system may be placed in proximity to a target of Purine Derivatives, for example, the spine, brain, colon, skin, heart, lung, eyes, or gastrointestinal tract, requiring therefore only a part of the systemic dose. The compositions of the present invention may optionally comprise a suitable amount of a physiologically acceptable carrier or vehicle. Such physiologically acceptable carriers or vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soy bean oil, mineral oil, sesame oil and the like. The transporters or physiologically acceptable vehicles can be a solution salt, acacia of rubber; 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, physiologically acceptable carriers or vehicles are sterile when administered to an animal. Water can be particularly useful when the Purine Derivative is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as carriers or liquid vehicles, particularly for injectable solutions. Suitable physiologically acceptable carriers or carriers also include starch, glucose, lactose, sucrose, gelatin, malt, rice, fluorine, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, milk powder, glycerol , propylene glycol, water, ethanol and the like. The compositions of the present invention, if desired may also contain minor amounts of wetting or emulsifying agents, or pH regulating agents. The compositions of the present invention can take the form of solutions, suspensions, emulsions, tablets, pills; granules, capsules, capsules containing liquid, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions and any other form suitable for use. In one modality, the composition It is in the shape of a capsule. Other examples of suitable physiologically acceptable carriers or carriers are described in Remington's Pharmaceutical Sciences Publication 1447-1676 (Alfonso R. Gennaro eds., 19th edition, 1995), incorporated herein by reference. In one embodiment, the Derivatives are formulated according to routine procedures as a composition adapted for administration to human beings. Compositions for oral administration may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs, for example. The compositions administered in oral form may contain one or more agents, for example, sweetening agents such as fructose, aspartame, saccharin; flavoring agents such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives to provide a pharmaceutically good taste preparation. In addition, when in tablet or pill forms, the compositions can be coated for disintegration and delayed absorption in the gastrointestinal tract, thereby providing a sustained action over a prolonged period of time. The selectively permeable membranes surrounding an osmotically active platform that drive a Purine Derivative are also suitable for compositions administered in oral form. In these Last platforms, the fluid from the environment surrounding the capsule can be drunk by the conduction compound, which expands to displace the agent or agent composition through an opening. These delivery platforms can provide an essentially zero order delivery profile as opposed to the adjusted profiles of immediate release formulations. A time delay material, such as glycerol monostearate or glycerol stearate can be used. The oral compositions may include standard carriers or carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate. In one embodiment, the transporters or vehicles are pharmaceutical grade. In another embodiment, Purine Derivatives can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise a sterile isotonic aqueous buffer. When necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to decrease pain at the site of injection. The components of the compositions can be supplied either separately or mixed together in a unit dosage form, for example, in the form of a powder dry leophilized or water-free concentrate in a hermetically sealed container, such as a vial or envelope indicating the amount of the Purine Derivative. When the Purine Derivatives will be administered by infusion, they can be supplied, for example, with an infusion bottle containing water or sterile pharmaceutical grade saline. When the Purine Derivatives are administered by injection, a vial of sterile water for injection or saline can be provided, so that the ingredients can be mixed before administration. Purine Derivatives can be administered by means of controlled release or sustained release or by delivery apparatuses that are known to those skilled in the art. Said dosage forms can be used to provide controlled or sustained release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes. , microspheres or a combination thereof to provide the desired release profile in various proportions. The sustained controlled release formulation known to those skilled in the art, including those described in the present invention, can be readily selected for use with the active ingredients of the present invention. Therefore, the present invention comprises simple unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel capsules and lozenges which are adapted for controlled or sustained release. In one embodiment, a controlled or sustained release composition comprises a minimum amount of a Purine Derivative to treat or prevent the condition, reduce the core temperature of an animal's body or protect the animal's heart against damage to the myocardium during cardioplegia in a minimum amount of time. The advantages of controlled or sustained release compositions include drug spreading activity, reduced dosing frequency and increased patient compliance. In addition, controlled or sustained release compositions can favorably affect the time of action release or other characteristics, such as blood levels of the Purine Derivative, and therefore can reduce the occurrence of adverse side effects. The controlled or sustained release compositions may initially release an amount of a Purine Derivative that rapidly produces the desired therapeutic or prophylactic effect, and gradually and continuously releases other amounts of the Purine Derivative to maintain this level of therapeutic or prophylactic effect for a period of time. of prolonged time. To maintain a constant level of the Derivative of Purine in the body, the Purine Derivative can be released from the dosage form in a range that will replace the amount of the Purine Derivative that is being metabolized and excreted from the body. The controlled or sustained release of an active ingredient can be stimulated through 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 conditions or physiological compounds. The amount of the Purine Derivative that is effective to treat or prevent a condition, reduce the core temperature of an animal's body, or protect the heart of an animal against damage to the myocardium during cardioplegia, can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can be optionally employed to help identify optimal dosage ranges. The precise dose that will be used may also depend on the route of administration and the severity of the condition being treated and may be decided according to the judgment of a medical specialist. However, suitable effective dose amounts range from about 10 micrograms to about 5 grams every 4 hours, although they are usually about 500 mg or less per 4 hours. In one embodiment the effective dose is approximately 0.01 mg, 0.5 mg, approximately 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. approximately 1.2 g. about 1.4 9. about 1.6 g. about 1.8 g, about 2.0 g. approximately 2.2 g. approximately 2.4 g. approximately 2.6 g- approximately 2.8 g. approximately 3.0 g. approximately 3.2 g. approximately 3.4 g. approximately 3.6 g. about 3.8 about 4.0 g, 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 may be administered for various periods of time, including, but not limited to, approximately every 2 hours, approximately every 6 hours, approximately every 8 hours, approximately every 12 hours, approximately every 24 hours, approximately every 36 hours, approximately every 48 hours, approximately every 72 hours, approximately every week, approximately every two weeks, approximately every three weeks, approximately every month, and approximately every two weeks months The number and frequency and dosages that correspond to a complete course of therapy can be determined according to the judgment of the medical specialist. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Purine Derivative is administered, the effective dose amounts correspond to the total amount administered. The amount of Purine Derivative that is effective to treat or prevent a Condition, or protect the heart of an animal against damage to the myocardium during cardioplegia typically ranges 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 of 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 to reduce the core temperature of an animal body normally ranges from about 1 μg / kg to about 10 mg / kg, in one embodiment, from about 0.1 mg / kg to about 5 mg / kg. kg of 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 Derivative is a component of a a solution that is useful for maintaining the availability of an ex vivo organ, the concentration of the Purine Derivative in the solution that is effective to maintain organ viability is between about 1 nM to about 1 mM. The Purine Derivatives can be tested in vitro or in vivo for the desired therapeutic or prophylactic activity, before being used in humans. Animal model systems can be used to manage safety and efficacy. The methods of the present invention for treating or preventing a Condition, reducing the core body temperature of an animal, or protecting the heart of an animal against damage to the myocardium during cardoplegia, may further comprise administering another therapeutic agent to the animal being treated. administering a Purine Derivative. In one embodiment, the other therapeutic agent is administered in an effective amount. The effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is within the abilities of those skilled in the art to determine the range of optimal effective amount of the other therapeutic agent. In one embodiment of the present invention, when administering another therapeutic agent to an animal, the effective amount of the Purine Derivative is less than what its effective amount might be, when the other therapeutic agent is not administer In this case, without intending to be limited by the theory, it is considered that the Purine Derivatives and the other therapeutic agent act in a synergistic manner. 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-spheroidal anti-inflammatory agents (NSAIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone , rofecoxib, colecoxib, 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, glibenclamide, glipizide, gazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidenediones, such as pioglitazone, rosiglitazone, and troglitazone; and a-glucosidase inhibitors, such as acarbose and miglitol.

In another embodiment, the other therapeutic agent is an agent-glaucoma. Examples of anti-glaucoma agents include, but are not limited to, aphidlonidine HCl, brimonidine tartrate, dipivefrin HCl, epinephrine HCl, betaxolol HCl, carteolol HCl, levobunolol HCl, methipranolol HCl, timolol, timolol maleate , Pilocarpine HCl, pilocarpine, dorzolamide HCl, brinzolamide and latanoprost. In an additional embodiment the other therapeutic agent is an anti-cardiovascular disease agent. Examples of anticardiovascular disease agents include, but are not limited to, carnitine; thiamine; lidocaine; amiodarone; procaineamide; mexiletine; bretyl 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 therapeutic agents include, but are not limited to, buprenorphine, meperidine, morphine, codeine, propoxyphene, fentanyl, sufentanil, etorphine hydrochloride, hydrocodone, hydromorphone, nalbuphine, butorphanol, oxycodone, aspirin, ibuprofen, sodium naproxen, 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 anti-emetic agent. Examples of useful anti-emetic agents include but are not limited to metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetyleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautin, bromopride, buclizine, clebopride, cyclizine. , dimenhydrinate, difenidol, dolasetron, meclizine, metalatal, metopimazine, nabilone, oxyperdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, or mixtures thereof. A Purine Derivative and the other therapeutic agent can act in an additive manner, or in a modality, in a synergistic manner. In one embodiment, a Purine Derivative is administered 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 administered concurrently. In another embodiment, an effective amount of a Purine Derivative is administered before or subsequent to the administration of an effective amount of another therapeutic agent. In this embodiment, a 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 preventive or therapeutic effect to treat or prevent a Condition, reducing the temperature Central body of an animal or protect the heart of an animal against damage to the myocardium during cardioplegia A composition of the present invention can be prepared using a method comprising mixing in additions a Purine Derivative and a physiologically acceptable carrier or vehicle Mixing with additions can be achieved using known methods for mixing in compound a compound (or salt) and a physiologically acceptable carrier or vehicle 46 PURINE DERIVATIVE THERAPEUTIC OR PROPHYLACTIC USES 46 1 TREATMENT OR PREVENTION OF CARDIOVASCULAR DISEASE A cardiovascular disease can be treated or prevented by the admi Administration of an Effective Amount of a Purine Derivative Cardiovascular diseases can be treated or prevented by administering an effective amount of a Purine Derivative include, but not limited to, atherosclerosis, congestive heart failure, circulatory attack, cardiomyopathy, heart transplant, cardioplegia, and a cardiac arrhythmia. In one modality, cardiovascular disease is a cardiac arrhythmia, congestive heart failure, circulatory attack or cardiomyopathy. In one modality, the cardiac arrhythmia is a tachycardia or an idiotypic arrhythmia. Still in another modality, tachycardia is atrial fibrillation, supraventricular tachycardia, atrial agitation, paroxysmal supraventricular tachycardia, paroxysmal atrial tachycardia, sinus tachycardia, atrioventricular nodal re-entry tachycardia, or tachycardia caused by Wolff-Parkinson-White syndrome. In a further embodiment, methods for treating a tachycardia include decreasing the animal's cardiac ventricular range to a range not less than about 40 palpitations per minute. In one embodiment, the methods are useful for decreasing the cardiac ventricular range of an animal to a range of from about 60 palpitations per minute to about 100 palpitations per minute. In another embodiment, the methods are useful for decreasing the cardiac range of an animal to a range of from about 100 palpitations per minute to about 140 palpitations per minute. In another embodiment, Purine Derivatives are useful for converting a cardiac arrhythmia into a normal breast rhythm. By Accordingly, the present invention comprises methods for converting a cardiac arrhythmia into a normal breast rhythm, comprising administering an effective amount of a Purine Derivative to an animal in need thereof. 4.6.2 PROTECTING THE HEART OF AN ANIMAL AGAINST CARDIAC DIAGNOSIS DAMAGE IN CARDIOPLEGIA In one embodiment, the present invention provides methods for inducing cardioplegia, which comprise administering to an animal in need thereof an effective amount of a cardioplegic agent and a Purine Derivative. Cardioplegic inducing agents useful in the present invention include, but are not limited to, potassium chloride, procaine, lidocaine, novocaine, bupivocaine, nicorandil, pinacidil, halothane, San Tomas solutions, Fremes' solution, 2,3-monoxime. -butanedione, and esmolol. In one embodiment, the agent that induces cardioplegia is lidocaine. In one embodiment, an agent that induces cardioplegia and a Purine Derivative are within the same composition. The methods of the present invention for inducing cardioplegia are useful to prevent or minimize the occurrence of myocardial damage during cardioplegia. In yet another embodiment, the present invention provides methods for protecting the heart of an animal against damage to the myocardium during cardioplegia, wherein the method comprises administering to an animal in need thereof an effective amount of a Purine Derivative. In yet another embodiment, the present invention provides methods for inducing cardioplegia in an animal while protecting the heart of an animal against damage to the myocardium during cardioplegia, wherein the method comprises administering to an animal in need thereof an effective amount of : (a) an agent that induces cardioplegia; and (b) a Purine Derivative. In one embodiment, the agent that induces cardioplegia is administered prior to the administration of the Purine Derivative. In another embodiment, the Purine Derivative is administered prior to the administration of the agent that induces cardioplegia. In a further embodiment, the cardioplegic inducing agent and the Purine Derivative are administered concurrently. In another modality, the agent that induces cardioplegia and Purine derivatives are administered in such a way that the Purine Derivative exerts its prophylactic effect of production against damage to the myocardium while the agent that induces cardioplegia exerts its cardioplegic effect. 4.6.3 TREATMENT OR PREVENTION OF A NEUROLOGICAL DISORDER A neurological disorder can be treated or prevented by administering 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, an attack disorder, such as epilepsy; pain, including acute post-operative pain, cancer pain, neuropathic pain, pain resulting from surgery, labor pain during childbirth, a fyscogenic pain syndrome, and headache, including migraine headache and headache in clusters; delirium and dementia such as Lewy body dementia, Alzheimer's disease, Pick's disease, or Creutzfeldt-Jakob disease; a sleep disorder such as insomnia, hypersomnia, sleep apnea syndrome, resting leg syndrome or parasomnia; a cranial nerve disorder such as Bell's palsy; a movement disorder such tremor, distoma, Tourette's syndrome, myoclonus, Huntington's disease, basal cortical degeneration, chorea, a drug-induced movement disorder, progressive supra-nuclear paralysis, Parkinson's disease or Parkinsonian syndrome, such as atrophy of the system multiple, Wilson's disease or multi-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 seizures; one upset neurophthalmic; a psychiatric disorder, including but not limited to, somatoform disorder, such as hypochondriasis or body dysmorphic disorder; a dissociation disorder such as panic disorder, phobic disorder or an obsessive-compulsive disorder; a mood disorder, such as depression or a bipolar disorder; personality disorder; psychosexual disorder, suicidal behavior, schizophrenia, brief psychotic disorder and hallucinatory disorder. In one embodiment, the disorder treated or prevented is epilepsy, pain, or seizures. In one embodiment, the methods of the present invention 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 OPHTHALM CONDITION An ophthalmic condition can be treated or prevented by administering 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, iscc retinopathy, diabetic retinopathy, and macular degeneration. acute 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 ISCC CONDITION An iscc condition can be treated or prevented by administering an effective amount of a Purine Derivative. Iscc 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 isca, isca, hepatic, mesenteric artery isca, intestinal isca, infarction at myocardium, critical limb isca, chronic critical limb isca, cerebral isca, acute cardiac isca, and iscc central nervous system disease, such as stroke or cerebral isca. In one embodiment, the iscc condition is myocardial isca, stable angina, unstable angina, seizures, iscc heart disease or cerebral isca. 4.6.6 TREATMENT OR PREVENTION OF REPERFUSION INJURY An impact injury can be treated or prevented by administering an effective amount of a Purine Derivative. Reperfusion injury can result after a naturally occurring episode, such as myocardial infarction or stroke, or during a surgical procedure where the blood flow in the vessels is intentional or not intentionally blocked. Reperfusion injuries can be treated or prevented by administering an effective amount of Purine Derivative including, but not limited to, intestinal reperfusion injury, myocardial reperfusion injury, and reperfusion injury resulting from cardiopulmonary bypass surgery, thorax-abdominal aneurysm repair surgery, carotid endarectomy surgery, or rrhagic attack one modality, reperfusion injury results from cardiopulmonary bypass surgery, thorax-abdominal aneurysm repair surgery, carotid endaretectomy surgery or rrhagic attack 4 6 7 TREATMENT OR PREVENTION OF DIABETES Diabetes can be treated or prevented by administering an effective amount of a Purine Derivative The 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-Dependent Tissue Diabetes Mellitus). Insulin), gestational diabetes, insulinopathy, diabetes due to pancreatic disease, diabetes associated with another endocrine disease (such as Gushing 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 modality, diabetes is Type I diabetes mellitus. In another modality, diabetes is Type II diabetes mellitus. 4.6.8 METHODS FOR REDUCING THE CENTER BODY TEMPERATURE OF AN ANIMAL In one embodiment, the present invention provides methods for reducing the core temperature of an animal's body, wherein the methods comprise administering to an animal in need thereof an effective amount. of a Purine Derivative. Reducing the core temperature of an animal's body is useful for slowing down metabolism or reducing oxygen consumption, particularly when the supply of oxygen to a tissue is inadequate. Examples of conditions characterized by an inadequate oxygen supply to a tissue include but are not limited to: (i) a medical procedure, such as cardiac surgery, brain surgery, organ transplantation, mechanical occlusion of the vascular supply, or vascular stenosis; (ii) a disorder or condition medical condition such as ischemia, a respiratory disorder, respiratory failure, pulmonary disorder, anemia, anaphylactic attack, hemorrhagic attack, dehydration, compartment syndrome, intravascular thrombus, septic attack, cystic fibrosis, lung cancer, attack, burn, or internal bleeding, (n) an injury such as drowning, a crush injury to one or more limbs, choking or choking, (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 comprises methods for encouraging the cardiac range with an animal during cardiac surgery, protecting the tissue in an animal of damage during surgery, heart or brain surgery, reducing intracranial hypertension caused by injury to the brain in an animal, or inducing hibe In an animal, wherein each method comprises administering an effective amount of a Purine Derivative to an animal in need of it. Reducing the core temperature of an animal's body is also useful in reducing the range of oxygen consumption of an animal. Accordingly, the present invention provides methods for reducing the range of oxygen consumption of an animal wherein the method comprises administering to an animal in need thereof an effective amount of a Derivative. of Purina. Reducing the core temperature of an animal's body is useful for treating or preventing tissue damage or attack, which results from an inadequate supply of oxygen to a cell, tissue, organ or organ system. In one embodiment, the core temperature of an animal's body is reduced to implement emergency resuscitation in an injured animal. In another embodiment, the core temperature of an animal's body is reduced before and / or during cardiac surgery. In a specific modality, the animal is a human child that undergoes pediatric cardiac surgery. In another embodiment, the core temperature of an animal's body is reduced to treat respiratory failure in an animal. In one embodiment, the core temperature of an animal's body is reduced to aid the metabolism of tissues in an animal, whose respiration and ventilation is facilitated by a ventilator. In a specific modality, the animal whose breathing and ventilation is facilitated by a ventilator is a pediatric human. In another specific modality, the animal whose breathing 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 preserve the viability of an organ after being eliminated from a donor and before the organ is transplanted into a recipient. In one modality, the donor and the recipient are the same. In another embodiment, an effective amount of a Purine Derivative can be administered to an animal awaiting an organ transplant to reduce the core temperature of the animal's body prior to or during organ transplantation. In one embodiment, core temperature of the animal body is reduced to a temperature of from about 4 ° C to about 34 ° C. In certain embodiments, the core temperature of an animal's body is reduced to about 34 ° C, up to about 30 ° C, up to about 25 ° C, up to about 20 ° C, up to about 15 ° C, to about 10 ° C, or up to about 4 ° C. In a specific embodiment, the core temperature of an animal's body is reduced to reduce therapeutic hypothermia. 4.6.9 TREATMENT OR PREVENTION OF OBESITY Obesity can be treated or prevented by administering an effective amount of a Purine Derivative. The types of obesity that can be treated or Preventable is administered to 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, obesity morbid, multigene obesity, and visceral obesity. In one modality, obesity is android obesity. 4.6.10 TREATMENT OR PREVENTION OF A CONSUMER DISEASE In one embodiment, the present invention provides methods for treating or preventing a wasting disease, wherein the methods comprise administering to an animal in need thereof an effective amount of a derivative. Purina. The types of wasting disease 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 are examples to aid in the understanding of the present invention, and, of course, should not be construed as specific limitations of the present invention described and claimed herein. Said variations of the present invention, including the substitution of all known equivalents up to now that were developed subsequently, which may be within the competence of those skilled in the art, and changes in the formulation or minor changes in the experimental design, will be considered as within the scope of the invention incorporated herein. 5. EXAMPLES Materials: [3H] NECA was obtained from Du Pont NEN, Dreieich, Germany. Other agonists or unlabeled adenosine receptor antagonists 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 the Publications of KIotz and Associates, J. Biol. Chem., 260: 14659-14664. 1985; Lohse et al., Naunyn-Schniedeberg's Arch. Pharmacol, 336: 204-210, 1987; and KIotz and associates, Naunyn-Schmiedeberg's Arch. Pharmacol, 357: 1-9, 1998. General methods: Magnetic resonance spectra were obtained instead of protons (NMR) from the 300 MHz Varian spectrometer and chemical changes were reported in parts per million. The compounds were characterized on NMR and Mass (MS) spectrum data bases. 6-chloroadenosine and 2,6- dichloroadenosine in TRC, Ontario, Canada, ACROS Organic, E.U.A., or Sigma-Aldrich (St. Loius, MO). 5.1 Example 1 Preparation of Compound l'-1 r-i 6-Chloroadenosine (1145 g, 4 mmol) was diluted with ethanol (50 mL) and the resulting solution was added to 1-hydroxymethylcyclopentylamine (1.0 g, 8 mmol). The resulting reaction mixture was heated to reflux and allowed to stir at reflux for about 15 hours. The resulting 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-1 (0.383 gm). 1 H NMR (DMSO-d 6): d 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, 1H), 3.50 - 3.58 (m, 1H), 3.62 - 3.68 (m, 2H), 3.95 (bs, 1H), 4.09 - 4.15 (m, 1H), 4.58 - 4.66 (m, 1H), 5.06 - 5.10 (m, 1H), . 18 (d, J - 4.2 Hz, 1H), 5.35 - 5.40 (m, 1H), 5.44 (d, J = 6 Hz, 1H), 5.87 (d, J = 6 Hz, 1H), 6.85 (s, 1H), 8.20 (s, 1H), 8.36 (s, 1 HOUR); MS (ES +): m / z 366 (M + 1). 5.2 Example 2 Preparation of Compound l'-19 r-i9 2,6-dichloroadenosine (0.4 gm, 0.0012 mol) was diluted with ethanol (25 ml) and to the resulting solution was added 1-hydroxymethylcyclopentylamine (1 gm, 0.008 mol). The resulting reaction mixture was heated to reflux and allowed to stir at reflux for about 6 hours. The resulting reaction mixture was subsequently cooled to room temperature and concentrated in vacuo. The resulting residue was purified using flash column chromatography (silica gel column using the 8% methanol-dichloromethane eluent) to provide Compound I-19 (365 mg, 83%). 1 H NMR (DMSO-de): d 1.51 - 1.62 (m, 2H). 1.71 - 1.82 (m, 4H), 2.10 -2.18 (m, 2H), 3.50 - 3.58 (m, 1H), 3.62 - 3.65 (m, 2H), 3.94 (bs, 1H), 4.12 (bs, 1H), 4.51 (d, J = 5.4 Hz, 1H), 4.97 (bs, 1H), 5.07 - 5.09 (m, 1H), 5.22 - 5.24 (m, 1H), 5.48 - 5.50 (m, 1H), 5.77 (d, J = 2.4 Hz, 1H), 5.80-5.82 (m, 1H), 7.42 (s, 1H), 8.40 (s, 1H); MS (ES +): m / z 400 (M + 1). 5.3 Example 3 Preparation of Compounds I-7, 1'-91a, I-92a, I-92b, I'- 93a, I-94a, I-95a, and I-95b Compounds I '-7, I' -91 a, I-92a, I-92b, I-93a, I-94a, I-95a, and I-I-95 b were prepared in accordance with the general methodology described in Examples 1 and 2 and elsewhere in the present invention. These compounds were characterized by mass spectroscopy as set forth in Table 1 below. Table 1 Mass Spectroscopic Characterization for Illustrative Purine Derivatives Compound MS (ES *): mz / IM + 11 l'-7 366.4 l'-91a 366.4 l'-92a 380.3 l'-92b 380.3 l'-93a 380.3 l'-94a 400.4 l'-95a 414.4 l' 95b 414.4 . 4 Example 4 Cell Culture and Membrane Preparation for Studies of Adenosine Receptor Linkage CHO cells stably transfected with the human adenosine receptor Ai, were grown and maintained in a Tabele Medium Modified by Dulbecco with a mixture of nutrients F12 (DMEM / F12) with nucleosides, containing fetal calf serum at 10%, penicillin (100 U / ml), streptomycin (100 μg / ml), L-glutamine (2 mM) and Genoticin (G-418, 0.2 mg / ml; A2B, 0.5 mg / ml) at a temperature of 37 ° C in air 5% C02 / 95%. Subsequently, the cells were divided 2 or 3 times a week in a ratio between 1: 5 and 1:20. The membranes for radioligand binding experiments were prepared from fresh or frozen cells as described in Kotz Publication and associates, Naunyn-Schmiedeberg's Arch. Pharmacol, 357: 1-9 (1998). The cell suspension was then homogenized in a non-homogenized homozygous or cold-water-free manner ((5 mmMM Tris / HCl, 2 mM EDTA, pH 7.4) and the resulting homogenate was rotated for 10 minutes (4 ° C) to 1,000 g. The membranes were then pelleted from the supernatant for 30 minutes at 100,000 g and re-suspended in 50 mM Tris / HCl buffer pH 7.4 (for A3 adenosine receptors: 50 mM Tris / HCl, 10 mM MgCl 2, 1 mM EDTA, pH 8.25) , were frozen in liquid nitrogen at a protein concentration of 1-3 mg / ml and stored at a temperature of -80 ° C. 5.5 Example 5 Adenosine Receptor Linker Studies The affinities of Purine Derivatives selected for the Ai adenosine receptor were determined by measuring the displacement of adenosine from [3 H] 2-chloro-N6-cyclopentyl-specific (Perkin-Elmer Life Sciences) bind in CHO cells transfected stably with recombinant human adenosine receptor Ai expressed as Ki (nM). The dissociation constants of the unlabeled compounds (K-values) were determined in competition experiments in 96-well microplates using the selective agonist Ai 2-chloro-N6- [3H] cyclopentyladenosine ([3H] CCPA, 1nM) for the characterization of the AT receptor link. The non-specific binding was determined in the presence of 100 μM R-PIA and 1 mM theophylline, respectively. For further details for the publication of KIotz and associates, Naunyn-Schmiedeberg's Arch. Pharmacol, 357: 1-9, 1998. All link data were calculated medianet non-linear curve fitting using the SCTFIT program (De Lean and associates, Mol Pharm. 1982, 2 _: 5-16). The results are presented in table 2 below. Table 2 Illustrative Purine Derivative Affinities for Recipients of adenosine A ^ A2A and A3 human Compound i (A?) a (nM) Ki (A7) D (nM) i (A3) c (nM) [3H] CCPA 083 2270 423 (055-125) (1950-2660 ) (321-558) 1-1 677 28100 7700 (600-763) (21200-37,300) (5480-10800) 1-19 647 24000 5960 (591-709) (17600-32,800) (4,140-8,600) Linkage displacement [Specific HJCCPA in CHO cells stably transfected with human recombinant adenosine receptor Ai, expressed as Ki (nM) b] [3H] NECA-specific linker in CHO cells transfected stably with recombinant human adenosine receptor A2 expressed as Ki (nM) c [3H] NECA-specific linker in HEK cells stably transfected with recombinant human adenosine A3 receptor, expressed as i (nM) All data are geometric averages with confidence intervals at 95 % in parentheses The data set forth in Table 2 demonstrate that the compounds l'-1 and l'-9, illustrative Purine Derivatives, selectively bind the adenosine receptor Ai, and therefore, are useful for treating or preventing a condition, making slowing the metabolic range of an animal, or protecting the heart of an animal against damage to the myocardium during cardioplegia 5 6 Example 6 Determination of Purine-Derived Effects in Septic Shock Male BALB / c mice (6 to 8 weeks of age) were used ) in studies to investigate the cytokine production induced by hpopolisacapdos and survival For cytokine production in mice were treated with a Derivative of illustrative Purina (0.03 mg / kg) in oral form by fattening 30 minutes, and then subjected to lipopolysaccharides (1 mg / kg i.p.) for 90 minutes. After this period, blood and serum were taken for analysis. Serum was diluted 1: 5 before being tested for cytokines using species-specific ELISA kits (R & D Systems) for chemokine MIP-1 and TNF-a cytokine levels, which are expressed as pg / ml. Survival study mice may be treated with an illustrative Purine Derivative (oral administration of 0.03 mg / kg) beginning 30 minutes before the mice are subjected to lipopolysaccharides (55 mg / kg i.p.). The survival of the mice was followed for 72 hours and expressed as a percentage of survival of mice at each time point. 5.7 Example 7 Determination of Anti-arrhythmia Effects of Purine Derivatives Cardiac Perfusion Male Sprague-Dawley rats (having a body weight of 250 to 300 g) were heparinized using sodium heparin (1,000 U / kg i.p.), followed by 10 minutes by introducing anesthesia through intraperitoneal administration of sodium pentobarbital (40 mg / kg). Once the animal was anesthetized, the thorax was opened, and the heart was rapidly removed and perfused through the ascending aorta using a Krebs-Ringer buffer consisting of NaCl (118 mmol / l), KCI (4.75 mmol / l), KH2P04 (1.18 mmol / l), MgSO4 (1.18 mmol / l), CaCl2 (2.5 mmol / l), NaHC03 (25 mmol / l), and glucose (11 mmol / l). A mixture of 95% 02 and 5% C02 was then bubbled at a temperature of 37 ° C through reperfusion (the heart was perfused initially at a constant pressure of 70 mm Hg). Approximately 10 minutes after the constant perfusion, perfusion was changed to a constant flow perfusion achieved using a micro tube pump. The perfusion pressure was maintained at the same level as the constant pressure perfusion, adjusting the flow range. Once the flow range was determined, it was maintained throughout the experiment. The hearts were stimulated by rectangular pulsations in a range of 5 Hz and duration of 2-milliseconds and twice the diastolic threshold value, supplied from a stimulus isolation unit (ADInstruments Ltd, Australia). Effect of Purine Derivatives on Ischemic-induced Arrhythmias Rat hearts were pre-used at a constant pressure of 70 mmHg without going from one side to the other as described above. The bipolar epicardial electrocardiogram (ECG) was recorded, placing two electrodes on the surface of the appendix and right apex. A steel cannula was used Stainless as an indifferent electrode The ECG and heart beat were continuously monitored and the data was recorded using a PowerLab data acquisition system (ADInstruments Ltd, Australia) together with a computer, and analyzed using the Chart 3 computer package. an equilibrium period of 20 minutes, regional ischemia was induced by ligating the left anterior descending coronary artery (LAD), and the ligature was released 30 minutes after occlusion. An illustrative interperfused Purine Derivative was applied 10 minutes prior to ligation. LAD and was present during LAD ligation An illustrative Purine Derivative will be tested at concentrations of 10, 30 and 100 pM 5 8 Example 8 Determination of Effect of Purine Derivative on function recovery after global ischemia / reperfusion Effect of a Derivative of Purina illustrative in the recovery of functions after ischemia / reperfusion Se p initially infused rat hearts at a constant pressure of 70 mm Hg using the procedure described above in Example 7 After 20 minutes of stabilization period, the hearts were subjected to ischemia without flow for 30 minutes followed by reperfusion 40 minutes in treated hearts, a Derivative of Illustrative purine for 10 minutes before the induction of ischemia. + Dp / dtmax was 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 Purine Derivatives on Pain Male mice (body weight of 25-35 grams) were placed in groups as follows: a first group which will be administered intraperitoneally with buprenorphine (0.3 mg / kg), a second group to which buprenorphine (1 mg / kg) will be administered intraperitoneally, a third group which will be given intraperitoneally an illustrative Purine Derivative (3 mg / kg), a fourth group to which an illustrative Purine Derivative (3 mg / kg) and buprenorphine (1.0 mg / kg) will be intraperitoneally co-administered, and a fifth group to which an illustrative Purine Derivative (3 mg) will be co-administered intraperitoneally. / kg) and buprenorphine (0.3 mg / kg). The analgesic effects in mice were measured using a taps analgesia meter on the IITC model 33 tail (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, treatment with compound or vehicle. The average log value of the two readings should be used for each time point. A baseline of between 2 and 4 seconds of latency for each mouse and a cut-off time of 10 seconds is adjusted for the maximum possible anagesia effect (% MPE). % MPE is calculated using the following formula:% MPE = [(post-drug-baseline value) / (cut-off time-baseline)] x 100. 5.10 Example 10 Determination of the effect of Purine Derivatives on pain Male mice (each having a body weight of 20-30 g) were subcutaneously administered 20 μl of a 1% formaldehyde solution in formaldehyde (prepared by diluting a 4% commercially available formalin solution [p / v]) in the dorsal region of its left hind leg. The mice were subsequently assigned either to a control group and vehicle administered, or to a treatment group. Each group was subsequently administered an illustrative Purine Derivative (1.0 mg / kg). Both groups of animals were subsequently monitored for a reaction during the 30 minutes post-treatment to determine how long the animal sucks the treated leg. The sucking time in the control group (animals pre-treated with vehicle) is subsequently prepared with the sucking 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 to 5 minutes post-treatment, and a late phase which lasts from 10 to 30 minutes post-treatment 5 11 Example 11 Determination of Effect of Purine Derivative on Pain BALB / C mice (6 to 8 weeks of age) were administered intrapeptoneally streptozotocm (40 mg / kg, once per day for 5 consecutive ) to induce diabetes (blood glucose levels greater than 200 mg / ml) Three weeks after the first streptozotocin injection, the animals were administered intrapeptoneally with an illustrative Purine Derivative (1 mg / kg) on a hind foot 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 points. time after the administration of an illustrative Purine Derivative 5 12 Example 12 Determination of the Effect of Purine Derivatives on Pain Male Wistar rats were anaesthetized (each weighing 200-2. 50 g, maintained under pathogen-free conditions at a temperature of 24-25 ° C and supplied with standard rat and water ad libitum) by intrapeptoneal administration of pentobarbital (50 mg / kg) and placed in a stereotaxic structure The membrane atlanto-occipital is exposed and a PE-10 catheter is inserted (7 5 cm) through an incision in the sub-arachnoidal 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 after surgery. The animals without neurological deficits were placed in a glass flexi observation chamber on a metal mesh surface and the mechanical threshold values of the plant surface of the paw can be determined, using Dynamic Plantar Aesthesiometer (Ugo Basile, Italy ) as indicated below: after acclimatization, a contact stimulation mode is placed under the leg of the animal, so that the filament is placed under the target area of the leg. Subsequently the filament is raised so that it contacts the soft part of the animal's leg and continuously exerts an upwardly increasing force on the leg until the animal removes the leg. The threshold value of the extraction of the leg is measured 5 minutes in this way in turns, and the average of the 5 values is calculated. After the control threshold value measurements are completed, carragene (3%, 100 μl) is administered subcutaneously in a hind paw, resulting in marked swelling and reddening of the treated paw. Three hours after Carragean administration, the threshold values are measured again. Subsequently the animals are divided into a control group (vehicle administered intrathecally) and a treatment group (administered in Intrathecal form an illustrative Purine Derivative in an injection volume of 10 μl). The threshold value determinations are repeated as described above at 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration of the vehicle or an illustrative Purine Derivative. 5.13 EXAMPLE 13 Effect Determination of Purine Derivatives in Pain Male CD rats (each weighing 220 g to 250 g) were prepared according to the procedure set forth in Z. Seltzer and associates publication, Pain, 43_: 205- 218 (1990). Subsequently the rats are anesthetized by intraperitoneal administration of sodium pentobarbital (50 mg / kg). An incision is made in the skin in 1/3 and 2/3 of the upper area of the left thigh of each rat, and the left sciatic nerve is exposed and released from the surrounding connective tissue. Subsequently an 8-0 nylon suture is used to tightly bind the left Asian nerve of each rat so that 1/3 to 1/2 dorsal of the nerve thickness is caught in the ligature. The incision was closed using a 4-0 sterile suture. Seven days after the surgery, the animals were placed in four groups: a first group to which the vehicle was administered (control group); a second group to which an illustrative Purine Derivative is administered at 0.1 mg / kg; a third group receiving buprenorphine at 0.3 mg / kg; and a fourth group to which an illustrative Purine Derivative was co-administered at 0 1 mg / kg and buprenorphine at 0 3 mg / kg. The animals in the four groups were evaluated for allodynia immediately before treatment and at 10, 20, 30 and 60 minutes after treatment using the Von Frey Hair test (GM Pitcher et al., J Neuroscí Methods, 87 185-93 (1999)) 5 14 E emplo g 14 Effect Determination of Purine Derivatives in Cardiac Frequency Rats were anesthetized Adult male Wistar (each weighing approximately 350 g to approximately 400 g) as in Example 12, were subsequently prepared to monitor blood pressure and heart rate. The heart rate of each animal was measured, then an intravenous Illustrative Purine Derivative through Femoral Vein in a dose of 1 ng / kg / mmuto, 10 ng / kg / mmuto, or 1000 ng / kg / minute (n = 2 animals per dose size) during a period of administration 20 minutes total measurement The heart rate of each animal was subsequently measured. The post-treatment heart rate was then compared with the heart rate pre-treatment 5 15 Example 15 Effect Determination of the Purine Derivative at Temperature Body Core Two male Sprague-Dawley rats of approximately 400 g each were kept at a temperature of 13 ° C and 20 mg / ml Compound I-1 dissolved in saline was slowly injected through a catheter jugular vein (JV) for approximately 2 minutes until reaching a dose of 15 mg / kg. After the rats fell asleep, 20 mg / ml of Compound I-1 was injected continuously through the jugular vein catheter via a syringe pump for 4 hours in a range of 1 ml / h. Subsequently the rats returned to their cages at room temperature. Rectal temperature, respiratory rate and behavior were recorded after 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 3A and table 3B.

Table 3A Parameters in Determination of the Effect of Purine Derivatives at Central Body Temperature up to 30 minutes Table 3B Parameters in Determination of the Effect of the Derivatives of Purine at the core temperature of the body after 30 minutes After the experiments, the animals were kept in the room and their behavior was observed. The data set forth in tables 3A and 3B indicates that compound l'-1, an illustrative Purine Derivative, reduces the core temperature of an animal's body. 5.16 Example 16 Determination of the Effect of Purine Derivatives in the Treatment or Prevention of Glaucoma with Intraocular Hypertension The effect of Compound l'-1 on intraocular pressure (IOP) was reviewed in New Zealand white rabbits. New Zealand white rabbits undergo a circadian or biological change in intraocular pressure, so that lower pressure values occur in the morning and peak pressure values occur in the afternoon. This biological rhythm is demonstrated in Figures 1 to 5 the day before the study (ie, t = -25 hours to = 0 hours). The consistency of the measurements is indicated by the fact that the intraocular pressure at t = -23 hours and t = 25 hours is essentially the same (see figures 1 to ). The compound l-1 was dissolved in saline, in concentrations 0.3, 1.0, 3.0, 10.0, and 30.0 mg / ml. Each rabbit was administered each dose level. A drop (approximately 100 μl) of the compound Compound I-1 salt solution was applied to the outer surface of one eye of each rabbit. Compound I-1 was administered at t = 0 hours, 3 hours after the end of the dark period of the animal housing (the lights come to the animal's shelter at t = -3 hours). Therefore, Compound I-1 was administered when the level of infraocular pressure was relatively lower than the other time points during the day and night. After administration with Compound l'-1, intraocular pressure did not increase to normal daily values (see figures from 1 to 5). For all administered concentrations of Compound I-1, the lowest infraocular pressure values were within the range of 3 to 4 mmHg, at a time point at which a New Zealand white mouse could be expected to have values of intraocular pressure of 11 to 13 mmHg. Therefore, treatment with Compound l'-1 resulted in a reduction of the intraocular pressure values through 8 to 10 mmHg, in relation to the expected values. The duration of the effect of Compound I-1 varies according to the magnitude of the dose. Recovery of intraocular pressure values to normal levels occurred at approximately t = 6 hours, when the administered concentration of Compound I-1 was 0.3 mg / ml (Fig. 1), and beyond t = 7 hours , when the administered concentration of Compound I-1 was 30 mg / ml (FIG. 5). No eye irritation was observed in any animal. The data set forth in Figures 1 to 5 indicate that Compound I-1, an illustrative Purine Derivative, reduces the intraocular pressure of an animal, and therefore, it is useful to treat or prevent glaucoma with intraocular hypertension. The present invention is not limited in scope to the specific embodiments described in the examples which are projected as illustrations of some aspects of the present invention, and any modalities that are functionally equivalent are within the scope of the present invention. In fact, those skilled in the art will appreciate various modifications of the present invention, in addition to those shown and described therein, and are intended to be within the scope of the appended claims. All references mentioned herein are incorporated by reference into the present invention.

Claims (1)

CLAIMS 1. A compound that has the formula and pharmaceutically acceptable salts thereof, wherein A is -CH 2 OH; B and C are -OH; D is: A and B are trans with respect to one another; B and C are cis with respect to one another; C and D are cis or trans with respect to one another; R1 is -H, -halo, -CN, -N (R) 2, -OR2, -SR2, -NHC (O) R2, NHC (O) N (R2) 2, -NHC (O) OR2, -C (0) OR2, -C (0) R2, -C (0) N (R2) 2, OC (0) N (R2) 2, -C (halo) 3, or -NO2; each R is independently -H, -C -? - C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, - (CH2) n-aryl, - (CH2) n- (monocyclic heterocycle of 3 to 7 members) , - (CH2) n- (bicyclic heterocycle of 8 to 12 members), - (CH2) n- (C3-Cß monocyclic cycloalkyl), - (CH2) n- (C3-C8 monocyclic cycloalkenyl), - (CH2) H - (C8-C12 bicyclic cycloalkyl), or - (CH2) n- (C8-C12 bicyclic cycloalkenyl); each n is an integer that fluctuates from 0 to 6; each p is an integer that fluctuates from 1 to 6; and each q is an integer ranging from 1 to 6. 2. The compound as described in claim 1, characterized in that q is 3. The compound as described in claim 1, characterized in that q is 4. 4. The compound as described in claim 1, wherein p is 1. 5. The compound as described in claim 2, wherein p is 1. 6. The compound as described in the claim. 3, where p is 1. 7. The compound as described in claim 1, characterized in that R1 is -H. 8. The compound as described in claim 1, characterized in that R1 is -halo. 9. The compound as described in claim 8, characterized in that R1 is -Cl. The compound as described in claim 2, wherein p is 1 and R 1 is -H 11 The compound as described in claim 2, wherein p is 1 and R 1 is -Cl 12 The compound as described in claim 3, wherein p is 1 and R 1 is -H 13 The compound as described in claim 3, wherein p is 1 and R 1 is -Cl 14 The compound as described in claim 1 having the structure (the') or a pharmaceutically acceptable salt thereof The compound as described in claim 14 having the structure 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, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 20. A method for treating an ophthalmic condition, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 21. A method for treating a cardiovascular disease, wherein the method comprises administering to a animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 22. A method for treating an ischemic condition, wherein the method comprises administering to an animal in need thereof effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 23. A method for treating diabetes, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 24. A composition comprising a cardioplegia induction agent, an amount effective of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1, and a physiologically acceptable carrier or vehicle. 25. A method for protecting the heart of an animal against damage to the myocardium during cardioplegia, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 26. A method to reduce the core temperature of the animal body, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 27. A method for reducing the consumption range of oxygen of an animal, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 28. A method of treating obesity, wherein the The method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 29. A method for treating or preventing a wasting disease, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the comp as set forth in claim 1. 30. A method for treating or preventing reperfusion injury, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound such as described in claim 1. 31. The method as described in the claim 30, characterized in that the reperfusion injury results from cardiopulmonary bypass surgery. 32. A method for treating tachycardia, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim 1. 33. The method as described in claim 32, characterized in that the tachycardia is atrial fibrillation, or a supraventricular tachycardia. 34. The method as described in claim 32, characterized in that the treatment includes decreasing the cardiac ventricular range of the animal to a range of from about 60 palpitations per minute to about 100 palpitations per minute. 35. The method as described in claim 32, characterized in that the treatment includes decreasing the cardiac ventricular range of the animal to a range of from about 100 palpitations per minute to about 140 palpitations per minute. 36. The method as described in claim 32, characterized in that the treatment includes decreasing the cardiac ventricular range of the animal to a range not less than about 40 palpitations per minute. 37. A method to convert a cardiac arrhythmia to a Normal sine rhythm, wherein the method comprises administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound as described in claim

1.