Orally active A1 adenosine receptor agonists

Details Orally active A1 adenosine receptor agonists Orally active A1 adenosine receptor agonists

1999-05-24

2003-06-10

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S027600, C536S027620

Reexamination Certificate

active

06576619

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of Invention
There is provided exceptionally stable and useful pro-drugs that are esters of N
6
-oxa, thia, thioxa and azacycloalkyl substituted adenosine derivatives that are selective adenosine type 1 receptor agonists, and as such, are potentially useful agents for the treatment cardiovascular diseases and central nervous system disorders.
2. Description of the Art
There are at least two subtypes of adenosine receptors in the heart: A
1
and A
2
. Each subtype effects different physiological functions. Stimulation of the A
1
adenosine receptor induces two distinct physiological responses. The first is the inhibition of the stimulatory effects of catecholamine. This effect is mediated via the inhibition of cyclic AMP synthesis. The second effect mediated by A
1
receptors is the slowing of the heart rate and impulse propagation through the AV node. The effect is independent of cAMP metabolism and is associated with A
1
adenosine receptor activation of the inwardly rectifying K+ channel. This effect is unique to the A
1
receptor; there is no role for the A
2
receptor in modulating the function of this channel. Stimulation of the adenosine A
1
receptor accordingly shortens the duration and decreases the amplitude of the action potential of AV nodal cells and subsequently prolongs the refractory period of the cells. The consequence of these effects is to limit the number of impulses conducted from the atria to the ventricles. This forms the basis of the clinical utility of A
1
receptor agonists for the treatment of supraventricular tachycardias, including atrial fibrillation, atrial flutter, and AV nodal re-entrant tachycardia.
The clinical utility of A
1
agonists therefore would be in the treatment of acute and chronic disorders of heart rhythm, especially those diseases characterized by rapid heart rate where the rate is driven by abnormalities in the atria. The disorders include but are not limited to atrial fibrillation, supra ventricular tachycardia and atrial flutter. Exposure to A
1
agonists causes a reduction in the heart rate and a regularization of the abnormal rhythm thereby restoring improved hemodynamic blood flow.
A
1
agonists, through their ability to inhibit the catecholamine induced increase in cAMP, should have beneficial effects in the failing heart where increased sympathetic tone causing enhanced cAMP has been associated with increased likelihood of ventricular arrhythmias and sudden death.
There are a number of A1 agonists disclosed in the prior art. However, the agonists disclosed are generally disclosed in the forms that are useful in the mammalian body. Because the useful forms may not always be stable, soluble or they may have other properties that make their incorporation into therapeutic dosage forms difficult, it is often necessary to identify compositions that are more easily incorporated into therapeutic dosage forms in order to provide the desired therapeutic effect. Therefore, there remains a need for specific A1 agonists precursors or pro-drugs that are converted in the body into useful therapeutic compositions.
Often, useful compounds may be altered to pro-drug form such that the desired compound is created in the body of the patient as the result of the action of metabolic or other biochemical process on the pro-drug. Such pro-drug forms typically demonstrate little or no activity in vitro assays. Some examples of pro-drug forms include ketal, acetal, oxime, and hydrazone forms of compounds which contain ketone or aldehyde groups, especially where they occur in the R.sub.1 group of the compounds of this invention.
SUMMARY OF THE INVENTION
An object of this invention are novel pro-drugs of heterocyclic substituted adenosine derivatives.
Another object of this invention are pro-drugs of heterocyclic substituted adenosine derivatives that are converted in the mammalian body to become useful A
1
receptor agonists.
Still another object of this invention are pro-drugs of heterocyclic substituted adenosine derivatives that are useful for treating supraventricular tachycardias, including atrial fibrillation, atrial flutter, and AV nodal re-entrant tachycardia in mammals and especially humans.
A composition of matter having the formula
wherein R
1
is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of N, 0, P and S—(O)
0-2
and wherein R
1
does not contain an epoxide group, and wherein R
2
R
2
′, and R
2
″ are independently selected from the group consisting of C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group 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 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
; wherein
R
20
is a member selected from the group consisting of H, C
1-15
alkyl,
C2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 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,
C2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 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.
In another embodiment, this invention is a method for stimulating coronary activity in a mammal experiencing a coronary electrical disorder that can be treated by stimulating an A
1
heart adenosine receptor by administering a therapeutically effective amount of the composition disclosed above to the mammal.
In still another embodiment, this invention is a pharmaceutical composition of matter comprising the composition of this invention and one or more pharmaceutical excipients.


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Jacobsen et al., “Adenosine Receptors: Pharmacology, Structure-Activity Relationships, and Therapeutic P

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