Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-04-12
2003-11-04
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S063000, C536S026600, C536S027610, C536S027620, C536S027630
Reexamination Certificate
active
06642210
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention includes N-pyrazole substituted 2-adenosine compounds that are useful as A
2A
receptor agonists. The compounds of this invention are vasodilating 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 A
2A
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 A
2
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
201
T1 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 A
2B
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 A
1
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 A
1
receptor by adenosine may be responsible for the nausea since the Al 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 A
2A
subtype receptors on coronary resistance vessels mediate the coronary dilatory responses to adenosine, whereas subtype A
2B
receptor stimulation relaxes peripheral vessels (note: the latter lowers systemic blood pressure). As a result there is a need for pharmaceutical compositions that are A
2A
receptor agonists that have no pharmacological effect as a result of stimulating the A
1
receptor in vivo. Furthermore, there is a need for A
2A
receptor agonists that have a short half-life, and that are well tolerated by patients undergoing pharmacological coronary stress evaluations.
SUMMARY OF THE INVENTION
In one aspect, this invention includes 2-adenosine N-pyrazole compounds that are useful A
2A
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.
REFERENCES:
patent: 4956345 (1990-09-01), Miyasaka et al.
patent: 4968697 (1990-11-01), Hutchison
patent: 5070877 (1991-12-01), Mohiuddin et al.
patent: 5189027 (1993-02-01), Miyashita et al.
patent: 5270304 (1993-12-01), Kogi et al.
patent: 5459254 (1995-10-01), Yamaguchi et al.
patent: 5593975 (1997-01-01), Cristalli
patent: 5705491 (1998-01-01), Yamada
patent: 5770716 (1998-06-01), Khan et al.
patent: 5939543 (1999-08-01), Morozumi et al.
patent: 6403567 (2002-06-01), Zablocki et al.
patent: 965411 (1975-04-01), None
patent: 0 354 638 (1990-02-01), None
patent: Hei 5-9197 (1993-01-01), None
Marumoto, et al., “Synthesis and Coronary Vasodilating Activity of 2-Substituted Adenosines”,Chem.. Pharm. Bull. 23(4): 759-774 (1975).
Marumoto, et al., “Synthesis and Enzymatic Activity of Adenosine 3′, 5′-Cyclic Phosphate Analogs”,Chem.. Pharm. Bull. 27(4) 990-1003 (1979).
Persson, et al., “Synthesis and Antiviral Effects of 2-Heteroaryl Substituted Adenosine and 8-Heteroaryl Substituted Adenosine Guanosine Derivatives”,Bioorganic&Medicinal Chemistry, 3:1377-1382 (1995).
Mager, et al., “Molecular simulation applied to 2-(N'alkylidenehydrazino)-and 2-(N'aralkylidenehydrazino) adenosine A2Agnonists”,Eur J. Med. Chem, 30:15-25 (1995).
Elzein Elfatih O.
Palle Venkata P.
Zablocki Jeff A.
Crane Lawrence E.
CV Therapeutics Inc.
McDonnell & Boehnen Hulbert & Berghoff
Wilson James O.
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