Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-09-23
2001-07-03
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S048000, C536S026210, C536S026230, C536S026260, C536S026700
Reexamination Certificate
active
06255292
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds that modulate cardiac muscle contractility, to methods for modulating cardiac muscle contractility, and to receptors that bind the compounds.
BACKGROUND OF THE INVENTION
Positive inotropic agents (i.e., agents which increase the contractility of cardiac muscle in a dose dependent manner) find use, inter alia, in the treatment of congestive heart failure and as vasodilators. Representative of the three classes of positive inotropic agents are the Na
+
/K
+
ATPase inhibitor digitalis, the &bgr;-adrenergic agonists dobutamine and dopamine, and the phosphodiesterase inhibitor amrinone.
Each of these classes of positive inotropic agents suffers from significant limitations. Digitalis displays a weak positive inotropic effect with narrow a therapeutic index, many adverse side effects, and undesirable interactions with other cardiac drugs. Dobutamine and dopamine cause desensitization of the &bgr;-adrenergic receptor-mediated positive inotropic response, are arrhythmogenic, and can only be administered intravenously. Orally active &bgr;-adrenergic agonists are only effective for a short period of time and lose efficacy due to desensitization. Phosphodiesterase inhibitors, such as milrinone, are potentially arrhythmogenic and have increased mortality relative to digitalis.
ATP is known to cause an inotropic effect in the heart, which is thought to be mediated by the P2 purinergic receptor (P2PR). To date there has been no detailed characterization of the specific P2PR involved, and no suitable cell model exists for the characterization of P2PR.
Consequently, there is a need in the art for positive inotropic agents which overcome the disadvantages associated with known agents, as well as a need for further information on the mechanisms and receptors associated with cardiac muscle contractility.
OBJECTS OF THE INVENTION
It is one object of the present invention to provide inotropic agents, that is, compounds that modulate (i.e., increase or decrease) cardiac muscle contractility.
It is another object of the invention to provide positive inotropic agents.
It is a further object to provide positive inotropic agents that have a broader therapeutic index than those currently available.
It is yet another object to provide positive inotropic agents having longer and more evenly sustained rates of release than those currently available.
It is a further object to provide positive inotropic agents having longer duration of action than those currently available.
It is yet another object to provide inotropic agents that are orally active.
It is a further object to identify and characterize receptors that bind the inotropic agents of the invention.
It is a another object of the invention to provide compounds having activity as vasodilators.
It is further object of the invention to provide methods for causing vasodilation.
SUMMARY OF THE INVENTION
These and other objects are accomplished by the present invention, which provides novel inotropic agents. In one aspect, the invention provides purine-containing inotropic agents having formula I or II:
wherein:
R
1
and R
2
, independently, are halogen or —R
6
—(R
7
)
p
—R
8
;
R
3
is H, halogen or —R
6
—(R
7
)
p
—R
8
;
R
4
is OH, SH or NH
2
;
R
5
is OH or acetamido;
R
6
is NH or S;
R
7
is alkylene having from 1 to 10 carbon atoms;
R
8
is H, NH
2
, CN, cycloalkyl having 3 to about 10 carbon atoms, or aryl having 3 to about 20 carbon atoms;
X and Y are independently N or CH;
n is 0 or 1;
q is 0 or 1;
m is 1 or 2; and
p is 0 or 1.
In certain preferred embodiments R
8
is —C
6
H
11
, —C
5
H
9
, —C
6
H
5
, —C
6
H
4
—NO
2
, or —CH[C
6
H
4
(CH
3
)][C
6
H
3
(OCH
3
)
2
]. In other preferred embodiments R
3
is H, and R
1
and R
2
are NH
2
, SH or Cl, and in further preferred embodiments X and Y are N or CH.
The sum of n, q, and m preferably is less than or equal to three. In preferred embodiments, n is 0, q is 0, and m is 2; n is 1, q is 0, and m is 2; n is 0, q is 0, and m is 1; or n is 0, q is 1, and m is 1. In some preferred embodiments m is 1 or 2, q is 1, n is 0, and R
4
is OH. In other preferred embodiments m is 1, q is 0, n is 0, and R
4
is SH or OH. In further preferred embodiments m is 2, q is 0, n is 0, and R
4
is OH. In yet further preferred embodiments m is 1 or 2, q is 0, n is 0, and R
4
is NH
2
.
The invention also provides compositions comprising the compound of formula I or II and a pharmaceutically acceptable carrier, adjuvant, or vehicle, preferably in an amount effective to increase cardiac muscle tissue contractility.
In another aspect, the invention provides compositions comprising the compounds of the invention, and methods for increasing contractility in cardiac muscle tissue. The methods generally comprise contacting cardiac muscle tissue with a compound of the invention and, optionally, measuring a rate of contraction associated therewith.
The invention also provides methods for increasing cellular contraction, comprising contacting a mammalian cell with a compound of the invention and, optionally, measuring a rate of contraction associated with the cell. Also provided are methods for treating a mammal in need of increased cardiac muscle contractility, comprising administering to the mammal a compound of the invention.
In another aspect, the invention provides methods and compositions for causing vasodilation. The methods generally comprise contacting a mammalian blood vessel with a compound of the invention, preferably by administration to a patient in need of vasodilation.
In a further aspect, the invention also provides isolated P2
y
-like purinergic receptors and compositions comprising a compound of the invention bound to P2
y
-like purinergic receptors.
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Crane L E
Gitomer Ralph
The Trustees of the University of Pennsylvania
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
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