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  Partial and full agonists of a1 adenosine receptorsUSPTO Application #: 20060135467Title: Partial and full agonists of a1 adenosine receptors Abstract: Disclosed are novel compounds that are partial and full A1 adenosine receptor agonists, useful for treating various disease states, in particular the supraventricular tachycardias, emesis, angina, myocardial infarction and hyperlipidemia. (end of abstract) Agent: Brian Lewis Cv Therapeutics, Inc. - Palo Alto, CA, US Inventors: Jeff Zablocki, Venkata Palle, Elfatih Elzein, Xiaofen Li USPTO Applicaton #: 20060135467 - Class: 514046000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Purines (including Hydrogenated) (e.g., Adenine, Guanine, Etc.), Adenosine Or Derivative The Patent Description & Claims data below is from USPTO Patent Application 20060135467. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] Priority is claimed to U.S. Provisional Patent Application Ser. No. 60/403,712, filed Aug. 15, 2002, and U.S. Provisional Patent Application Ser. No. 60/450,094, filed Feb. 25, 2003, the complete disclosures of which are hereby incorporated by reference. FIELD OF THE INVENTION [0002] The present invention relates to novel compounds that are partial or full A.sub.1 adenosine receptor agonists, and to their use in treating mammals for various disease states, including cardiovascular diseases, in particular arrhythmia and the prevention of sudden death resulting from arrhythmia, ischemia, and CNS disorders including pain, epilepsy, and emesis. A.sub.1 adenosine receptor agonists are antilipolytic agents, and are useful for treating metabolic disorders, including diabetes and obesity. The invention also relates to methods for their preparation, and to pharmaceutical compositions containing such compounds. BACKGROUND [0003] Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A.sub.1, A.sub.2a, A.sub.2b, and A.sub.3, all of which modulate important physiological processes. For example, A.sub.2A adenosine receptors modulate coronary vasodilation, A.sub.2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A.sub.2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153), and A.sub.3 adenosine receptors modulate cell proliferation processes. [0004] A.sub.1 adenosine receptor agonists modulates the cardiostimulatory effects of catecholamine (mediated via the inhibition of adenylate cyclase), and slow the heart rate (HR) and prolong impulse propagation through the AV node, which is due in great part to activation of I.sub.KAdo. (B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 and J. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997) P 2-10). Stimulation of the A.sub.1 adenosine receptor shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of A.sub.1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. [0005] Elevated serum levels of non-esterified free fatty acid (NEFA) are detrimental to both the mechanical and electrical function of the heart, and A.sub.1 adenosine receptor agonists are potent and efficacious inhibitors of lipolysis. Importantly, because A.sub.1 adenosine receptor agonists are more potent in adipose tissue that in heart tissues, they decrease lipolysis at concentrations that do not affect heart rate. Thus, A.sub.1 adenosine receptor agonists are useful for treating metabolic disorders such as non-insulin-dependent diabetes mellitus and obesity via their anti-lipolytic activity. The antilipolytic effect of adenosine A.sub.1 receptor agonists is also useful in the management of congestive heart failure. Furthermore, A.sub.1 adenosine receptor agonists are protective against cardioischemia. A.sub.1 adenosine receptor agonists are also useful as chemotherapeutics in the treatment of CNS disorders including epilepsy (anticonvulsant activity) and ischemia. [0006] Accordingly, it is an object of this invention to provide compounds that are potent full A.sub.1 adenosine receptor agonists or partial A.sub.1 adenosine receptor agonists. Preferred compounds of the invention are selective for the A.sub.1 adenosine receptor, which minimizes undesired side effects related to stimulation or antagonism of the other adenosine receptors. SUMMARY OF THE INVENTION [0007] Accordingly, in a first aspect, the invention relates to compounds of Formula I: [0008] wherein: [0009] R.sup.1 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0010] R.sup.2 is hydrogen, halo, trifluoromethyl, or cyano; [0011] R.sup.3 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, [0012] R.sup.4 and R.sup.5 are independently hydrogen or optionally substituted acyl; [0013] X is a covalent bond or lower alkylene optionally substituted by cycloalkyl; [0014] X.sup.1 is a covalent bond or alkylene. [0015] Y is a covalent bond or lower alkylene optionally substituted by hydroxy or cycloalkyl; and [0016] Z is --C.ident.C--, --R.sup.6C.dbd.CR.sup.7--, or --CHR.sup.6CHR.sup.7--, in which R.sup.6 and R.sup.7 at each occurrence are hydrogen or lower alkyl [0017] A second aspect of the invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one pharmaceutically acceptable excipient. [0018] A third aspect of the invention relates to a method of using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be effectively treated with a partial or full selective A.sub.1 adenosine receptor agonist. Such diseases and conditions include at least one of the following; supraventricular tachycardia, including atrial fibrillation, and atrial flutter, ischemia, including that due to stable and unstable angina, congestive heart failure, myocardial infarction, disorders of the CNS including epilepsy and stroke, metabolic disorders, such as obesity and diabetes, or the sequela of diabetes or congestive heart failure specifically hyperlipidemia, which is alleviated by the antilipolytic effect of A.sub.1 agonists on adipocytes; and the treatment of nausea (emesis). [0019] A fourth aspect of this invention relates to methods of preparing the compounds of Formula I. [0020] Of the compounds of Formula I, one preferred class includes those compounds in which Z is --C.ident.C--, particularly those compounds in which X, X.sup.1 and Y are covalent bonds. A preferred group within this class includes those compounds in which R.sup.1 is optionally substituted cycloalkyl optionally substituted heterocyclyl, or optionally substituted heteroaryl, and R.sup.2, R.sup.4 and R.sup.5 are hydrogen. [0021] A preferred subgroup includes those compounds of Formula I in which R.sup.3 is hydrogen or optionally substituted aryl, especially optionally substituted phenyl. Particularly preferred compounds within this subgroup are those compounds in which R.sup.1 is cycloalkyl, especially cyclopentyl or hydroxycyclopentyl, or optionally substituted heterocyclyl, especially tetrahydrofuran-3-yl, and R.sup.3 is hydrogen. Other preferred compounds within this subgroup includes those compounds of Formula I in which R.sup.3 is optionally substituted phenyl. Particularly preferred are those compounds in which R.sup.1 is cycloalkyl, especially cyclopentyl, or optionally substituted heterocyclyl, especially tetrahydrofuran-3-yl, and R.sup.3is 2-fluorophenyl or 2-trifluoromethylphenyl. [0022] Another preferred subgroup includes those compounds of Formula I in which R.sup.3 is optionally substituted aryl. Particularly preferred compounds within this subgroup are those compounds in which R.sup.1 is cycloalkyl, especially cyclopentyl, or optionally substituted heterocyclyl, especially tetrahydrofuran-3-yl. Preferred R.sup.3 groups include optionally substituted thienyl, especially 5-chlorothien-2-yl. [0023] Of the compounds of Formula I, another preferred class includes those compounds in which Z is --R.sup.6C.dbd.CR.sup.7--, particularly those compounds in which R.sup.6 and R.sup.7 are hydrogen and X, X and Y are covalent bonds. A preferred group within this class includes those compounds in which R.sup.1 is optionally substituted cycloalkyl, and R.sup.2, R.sup.4 and R.sup.5 are hydrogen. A preferred subgroup includes those compounds of Formula I in which R.sup.3 is optionally substituted aryl or optionally substituted heteroaryl. Particularly preferred are those compounds in which R.sup.3 includes optionally substituted phenyl, especially phenyl or 2-methylphenyl, or optionally substituted thienyl, especially 5-chlorothien-2-yl. Definitions and General Parameters [0024] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0025] The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like. [0026] The term "substituted alkyl" refers to: [0027] 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, for example 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or [0028] 2) an alkyl group as defined above that is interrupted by 1-10 atoms independently chosen from oxygen, sulfur and NR.sub.a--, where R.sub.a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF.sub.3, amino, substituted amino, cyano, or --S(O).sub.nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or [0029] 3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-10 atoms as defined above. [0030] The term "lower alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like. [0031] The term "substituted lower alkyl" refers to lower alkyl as defined above having 1 to 5 substituents, for example 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above. [0032] The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, for example having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and --CH(CH.sub.3)CH.sub.2--) and the like. Continue reading... Full patent description for Partial and full agonists of a1 adenosine receptors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Partial and full agonists of a1 adenosine receptors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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