This application is a continuation of co-pending U.S. application Ser. No. 11/252,760, filed on Oct. 18, 2005, which is a continuation of co-pending U.S. application Ser. No. 10/652,378, filed on Aug. 29, 2003, which is a continuation of U.S. application Ser. No. 10/018,446, filed on Apr. 12, 2002, now U.S. Pat. No. 6,642,210, which is a 371 of PCT/US00/40281, filed on Jun. 21, 2000, which is a continuation-in-part of U.S. application Ser. No. 09/338,185, filed on Jun. 22, 1999, now U.S. Pat. No. 6,403,567 the specifications of each of which are incorporated herein by reference.
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OF THE INVENTION
1. Field of Invention
This invention includes N-pyrazole substituted 2-adenosine compounds that are useful as A2A receptor agonists. The compounds of this invention are vasodialating agents that are useful as heart imaging aids that aid in the identification of mammals, and especially humans who are suffering from coronary disorders such poor coronary perfusion which is indicative of coronary artery disease (CAD). The compounds of this invention can also be used as therapeutics for coronary artery disease as well as any other disorders mediated by the A2A receptor.
2. Description of the Art
Pharmacological stress is frequently induced with adenosine or dipyridamole in patients with suspected CAD before imaging with T1 scintigraphy or echocardiography. Both drugs effect dilation of the coronary resistance vessels by activation of cell surface A2 receptors. Although pharmacological stress was originally introduced as a mean of provoking coronary dilation in patients unable to exercise, several studies have shown that the prognostic value of 201T1 or echocardiographic imaging in patients subjected to pharmacological stress with adenosine or dipyridamole was equivalent to patients subjected to traditional exercise stress tests. However, there is a high incidence of drug-related adverse side effects during pharmacological stress imaging with these drugs such as headache and nausea, that could be improved with new therapeutic agents.
Adenosine A2B and A3 receptors are involved in a mast cell degranulation and, therefore, asthmatics are not give the non-specific adenosine agonists to induce a pharmacological stress test. Additionally, adenosine stimulation of the A1 receptor in the atrium and A-V node will diminish the S-H interval which can induce AV block (N. C. Gupto et al.; J. Am Coll. Cardiol; (1992) 19: 248-257). Also, stimulation of the adenosine A1 receptor by adenosine may be responsible for the nausea since the A1 receptor is found in the intestinal tract (J. Nicholls et al.; Eur. J. Pharm. (1997) 338(2) 143-150).
Animal data suggests that specific adenosine A2A subtype receptors on coronary resistance vessels mediate the coronary dilatory responses to adenosine, whereas subtype A2B receptor stimulation relaxes peripheral vessels (note: the latter lowers systemic blood pressure). As a result there is a need for pharmaceutical compositions that are A2A receptor agonists that have no pharmacological effect as a result of stimulating the A1 receptor in vivo. Furthermore, there is a need for A2A receptor agonists that have a short half-life, and that are well tolerated by patients undergoing pharmacological coronary stress evaluations.
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OF THE INVENTION
In one aspect, this invention includes 2-adenosine N-pyrazole compounds that are useful A2A receptor agonists.
In another aspect, this invention includes pharmaceutical compounds including 2-adenosine N-pyrazole that are well tolerated with few side effects.
Still another aspect of this invention are N-pyrazole compounds that can be easily used in conjunction with radioactive imaging agents to facilitate coronary imaging.
In one embodiment, this invention includes 2-adenosine N-pyrazole compounds having the following formula:
In another embodiment, this invention includes methods for using compounds of this invention to stimulate coronary vasodilatation in mammals, and especially in humans, for stressing the heart induced steal situation for purposes of imaging the heart.
In still another embodiment, this invention is a pharmaceutical composition comprising one or more compounds of this invention and one or more pharmaceutical excipients.
DESCRIPTION OF THE FIGURES
FIG. 1A is a analog record of the increase in coronary conductance caused by Compound 16 of this invention before and after infusions of CPX and ZM241385;
FIG. 1B is a summary of the data shown in FIG. 1A showing that CPX did not but that ZM241385 did attenuate the increase in coronary conductance caused by Compound 16 of this invention. In FIG. 1B, the bars represent mean±SEM of single measurement from 6 rat isolated perfused hearts;
FIG. 2 is a concentration response curve for the A1 adenosine receptor (AdoR)-mediated negative dromotropic (AV conduction time) and A2A AdoR-mediated vasodialator (increase coronary conductance) effects of Compound 16 in rat isolated perfused hearts. Symbols and error bars indicate means±SEM of single determination from each of four hearts. EC50 value (potency) is the concentration of Compound 16 that causes 50% of maximal response;
FIG. 3 is a concentration response curve for the A1 adenosine receptor (AdoR)-mediated negative dromotropic (AV conduction time) and A2A AdoR-mediated vasodialator (increase coronary conductance) effects of Compound 16 in guinea pig isolated perfused hearts. Symbols and error bars indicate means±SEM of single determination from each of four hearts. EC50 value (potency) is the concentration of Compound 16 that causes 50% of maximal response; and
FIG. 4 is a plot of the effect of CVT510, an A1 adenosine receptor agonist and Compound 16 of this invention, an A2A adenosine receptor agonist on atrioventricular (AV) conduction time in rat isolated perfused hearts.
DESCRIPTION OF THE CURRENT EMBODIMENT
This invention includes a class of 2-adenosine N-pyrazole having the formula: