C-pyrazole 2A A receptor agonists

Details C-pyrazole 2A A receptor agonists C-pyrazole 2A A receptor agonists

1999-06-22

2001-04-10

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S045000, C514S047000, C536S027300, C536S027600, C536S027610, C536S027700

Reexamination Certificate

active

06214807

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of Invention
This invention includes C-pyrazole compositions that are useful as A
2A
receptor agonists. The compositions of this invention are vasodialating agents that are useful in heart imaging to aid in the identification of mammals, and especially humans who are suffering from disorders such poor coronary perfusion which is indicative of coronary artery disease (CAD). The compositions of this invention can also be used as therapeutics for coronary artery disease.
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 A
3
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 mode 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 maybe responsible for the nausea since the A
1
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
2
A 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 C-pyrazole compositions that are useful A2A receptor agonists.
In another aspect, this invention includes pharmaceutical compositions including 2-adenosine C-pyrazole that are well tolerated with few side effects.
Still another aspect of this invention are C-pyrazole compositions that can be easily used in conjunction with radioactive imaging agents to facilitate coronary imaging.
In one embodiment, this invention includes C-pyrazole compositions having the following formula:
In another embodiment, this invention includes methods for using compositions of this invention to stimulate coronary vasodilatation in mammals, and especially in humans, for stressing the heart to induce a steal situation for purposes of imaging the heart.
In still another embodiment, this invention is a pharmaceutical composition of matter comprising one or more compositions of this invention and one or more pharmaceutical excipients.
DESCRIPTION OF THE CURRENT EMBODIMENTS
This compositions of this invention include a class of 2-adenosine C-pyrazole compounds having the following formula:
wherein R
1
is —CH
2
OH, and —C(═O)NR
5
R
6
;
R
2
is selected from the group consisting of hydrogen, C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, NO
2
, heterocyclyl, aryl, heteroaryl, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, SO
2
NR
20
COR
22
, SO
2
NR
20
CO
2
R
22
, SO
2
NR
20
CON(R
20
)
2
, N(R
20
)
2
NR
20
COR
22
, NR
20
CO
2
R
22
, NR
20
CON(R
20
)
2
, NR
20
C(NR
20
)NHR
23
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, CONR
20
SO
2
R
22
, NR
20
SO
2
R
22
, SO
2
NR
20
CO
2
R
22
, OCONR
20
SO
2
R
22
, OC(O)R
20
, C(O)OCH
2
OC(O)R
20
, and OCON(R
20
)
2
and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO
2
, alkyl, CF
3
, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR
22
, NR
20
SO
2
R
22
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, NR
20
CON(R
20
)
2
, OC(O)R
20
, OC(O)N(R
20
)
2
, SR
20
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, CN, or OR
20
;
R
3
, R
4
are individually selected from the group consisting of hydrogen, C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, halo, NO
2
, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, SO
2
NR
20
COR
22
, SO
2
NR
20
CO
2
R
22
, SO
2
NR
20
CON(R
20
)
2
, N(R
20
)
2
NR
20
COR
22
, NR
20
CO
2
R
22
, NR
20
CON(R
20
)
2
, NR
20
C(NR
20
)NHR
23
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, CONR
20
SO
2
R
22
, NR
20
SO
2
R
22
, SO
2
NR
20
CO
2
R
22
, OCONR
20
SO
2
R
22
, OC(O)R
20
, C(O)OCH
2
OC(O)R
20
, and OCON(R
20
)
2
wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents individually selected from the group consisting of halo, NO
2
, heterocyclyl, aryl, heteroaryl, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, SO
2
NR
20
COR
22
, SO
2
NR
20
CO
2
R
22
, SO
2
NR
20
CON(R
20
)
2
, N(R
20
)
2
NR
20
COR
22
, NR
20
CO
2
R
22
, NR
20
CON(R
20
)
2
, NR
20
C(NR
20
)NHR
23
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, CONR
20
SO
2
R
22
, NR
20
SO
2
R
22
, SO
2
NR
20
CO
2
R
22
, OCONR
20
SO
2
R
22
, OC(O)R
20
, C(O)OCH
2
OC(O)R
20
, and OCON(R
20
)
2
and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO
2
, alkyl, CF
3
, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR
22
, NR
20
SO
2
R
22
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, NR
20
CON(R
20
)
2
, OC(O)R
20
, OC(O)N(R
20
)
2
, SR
20
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, CN, or OR
20
;
R
5
and R
6
are each individually H, C
1-15
alkyl with from 1 to 2 substituents independently selected from the group consisting of halo, NO
2
, heterocyclyl, aryl, heteroaryl, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, SO
2
NR
20
COR
22
, SO
2
NR
20
CO
2
R
22
, SO
2
NR
20
CON(R
20
)
2
, N(R
20
)
2
NR
20
COR
22
, NR
20
CO
2
R
22
, NR
20
CON(
20
)
2
, NR
20
C(NR
20
)NHR
23
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, CONR
20
SO
2
R
22
, NR
20
SO
2
R
22
, SO
2
NR
20
CO
2
R
22
, OCONR
20
SO
2
R
22
, OC(O)R
20
, C(O)OCH
2
OC(O)R
20
, and OCON(R
20
)
2
and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO
2
, alkyl, CF
3
, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR
22
, NR
20
SO
2
R
22
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, NR
20
CON(R
20
)
2
, OC(O)R
20
, OC(O)N(R
20
)
2
, SR
20
, S(O)R
22
, SO
2
R
22
, SO
2
N(
20
)
2
, CN, or OR
20
,
R
20
is selected from the group consisting of H, C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C
1-6
alkyl, CF
3
, aryl, and heteroaryl; and
R
22
is a member selected from the group consisting of C
1-15
alkyl, C
2-15
alkenyl, C
2-15
al

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