Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-18
2001-07-24
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S079000
Reexamination Certificate
active
06265421
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a method for increasing coronary flow. Particularly, the invention relates to a method for obtaining direct dilatation of the coronary arteries by administering a phospholamban inhibitor as the active compound. The present invention also relates to novel phospholamban inhibitors, pharmaceutical compositions containing these compounds and new intermediates. Novel phospholamban inhibitors are also useful in the treatment of heart failure and stunned myocardium.
Contraction of the muscle cell is controlled by the amount of free cytosolic calcium interacting with calmodulin in smooth muscle cells or with troponin C in cardiac and skeletal muscle cells. These calcium-activated proteins trigger a cascade of events leading to cell shortening and muscle contraction.
One of the most important enzymes which aids to terminate or prevent the muscle contraction is the Ca2+-ATPase located inside the cell in the sarcoplasmic reticulum (SR). This enzyme transfers cytosolic calcium against the concentration gradient into the intracellular calcium storages. The function of the SR Ca
2+
-ATPase (SERCA) is controlled by a small protein called phospholamban. When phospholamban is unphosphorylated, it inhibits the SERCA. In contrast, when phosphorylated, phospholamban does not inhibit this calcium pump. The removal of the inhibitory effect of phospholamban is seen as a stimulation of the calcium uptake into the SR, since some of the SERCA molecules are all the time under the inhibitory control of phospholamban.
Phospholamban has been shown to have an important role in the cardiac muscle (Lindemann, J. P. et al., “Beta-adrenergic stimulation of phospholamban phosphorylation and Ca
2+
-ATPase activity in guinea pig ventricles”, J. Biol. Chem. 258:464-471, 1983) and in the slow skeletal muscles, whereas the fast skeletal muscle does not express phospholamban at all (Hoh, J. F. Y, “Muscle fiber types and function”, Current Opinion in Rheumatology, 4:801-808, 1992). Moreover, phospholamban is expressed in mouse aorta (Lalli, J. et al., “Targeted ablation of the phospholamban gene is associated with a marked decrease in sensitivity in aortic smooth muscle”, Circ. Res. 80(4): 506-513, 1997) and thereby it is thought that phospholamban controls SERCA in peripheral vascular tissue.
Through its inhibitory effects on the SERCA present in the cardiac tissue phospholamban represses both the rates of relaxation and contraction in the mammalian heart. Therefore, a compound capable of relieving the inhibitory effects of phospholamban on cardiac SERCA, e.g. by interrupting phospholamban-SERCA interaction, would be useful in the treatment of heart failure.
Evidence was very recently given that PLB is present in aortic endothelial cells (Sutliff, R. L. et al., “Functional and biochemical evidence for modulation of endothelial cell function by phospholamban”, FASEB Journal 12 (5):A957, 1998), where it modulates the activity of the isoform of SERCA present on the endoplasmic reticulum. It was also shown that a decreased activity of the endoplasmic reticulum calcium pumping in aortic endothelial cells is leading to defective endothelium-dependent relaxation of aortic vascular smooth muscle (Liu, L. H. et al., “Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca
2+
signalling in mice lacking sarco(endo)plasmic reticulum CA
2+
-ATPase isoform 3”, J. Biol. Chem. 272(48):30538-30545, 1997).
There is no published evidence of the presence of phospholamban in the endothelial cells of coronary arteries.
SUMMARY OF THE INVENTION
It has now been found that compounds of formulae (I) or (II) are effective in relieving the inhibitory effects of phospholamban on cardiac SR Ca
2+
-ATPase (SERCA). The compounds of formulae (I) or (II) act as phospholamban inhibitors through direct binding to the phospholamban protein. Thereby, compounds of formulae (I) or (II) eliminate the inhibitory action of phospholamban on the SERCA like the protein kinases as they phosphorylate phospholamban.
Furthermore, it was surprisingly found that the phospholamban inhibitors of formula (I) or (II) increased coronary flow in isolated paced guinea-pig heart perfused with constant pressure. The magnitude of the effect on coronary flow markedly exceeded the increasing effects of the compounds on the relaxation and contraction velocities of the left ventricle of the heart indicating that compounds of formula (I) or (II) directly dilate the coronary arteries. The effect of compounds (I) or (II) on coronary flow preceded the other effects confirming that the coronary dilatation was due to the direct effect of the compounds on the coronary arteries. Furthermore, it was found that the vasodilatory effect of the phospholamban inhibitors of (I) or (II) is due to an endothelial-mediated mechanism. Therefore, we propose that phospholamban inhibitors induce vasodilatation and enhance the coronary flow by blocking the inhibitory effect of PLB on SERCA on the endoplasmic reticulum of the endothelial cells of the coronary arteries.
Having the unexpected ability to directly dilatate the coronary arteries, phospholamban inhibitors, such as compounds (I) or (II), are useful in the treatment of conditions where an increase in the coronary flow is desired, e.g. in coronary heart disease and in hemodynamic crisis in which the low aortic blood pressure decreases coronary perfusion pressure.
Compounds of the present invention have the structure represented by formulae (I) or (II):
in which
R
1
is hydrogen, alkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, halogenalkyl, alkoxy, COR
10
, CONR
10
R
11
, OR
10
, S(O)
m
R
10
, NR
10
COR
11
or NR
10
R
11
, where R
10
is hydrogen, alkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, halogenalkyl, alkoxy or hydroxy and R
11
is hydrogen, alkyl, aryl, arylalkyl, alkoxy, aryloxy, hydroxy or acyl, or in case where X is NR
11
, can R
1
also be carboxylalkyl,
R
6
is hydrogen, alkyl, alkenyl, aryl, arylalkyl,
R
2
and R
7
mean hydrogen, alkyl, aryl, arylalkyl, alkenyl, COR
10
, CONR
10
R
11
, halogen, trifluoromethyl, nitro or cyano, where R
10
and R
11
are defined as above,
R3 is hydrogen, alkyl, aryl or arylalkyl,
A means alkyl or substituted alkyl,
m is 0-2 and n is 1-3,
Y means O, NR11 or S, where R11 is the same as above,
X means O, NR11 or S, where R11 is the same as above,
R
4
, R
5
, R
8
and R
9
mean independently one of the following groups:
or in case where X is NR
11
, can R
4
, R
5
, R
8
and R
9
also independently mean HOOC—, R
12
OOC—, H
2
NCO— or HOHNCO— wherein R
12
means alkyl, arylalkyl or aryl,
and wherein each aryl residue defined above by itself or as part of another group may be substituted,
and pharmaceutically acceptable salts and esters thereof.
In one class of preferred compounds and pharmaceutically acceptable salts and esters thereof are compounds of formula (I) wherein R2 is hydrogen. In a subclass of this class of compounds and pharmaceutically acceptable salts and esters thereof R1 is hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
6-10
aryl, C
7-12
arylalkyl, C
1-6
hydroxyalkyl, C
1-6
halogenalkyl or C
1-6
alkoxy. In a group of this subclass of compounds and pharmaceutically acceptable salts and esters thereof, Y is O or S, preferably O; and X is O. In another group of this subclass of compounds and pharmaceutically acceptable salts and esters thereof, Y is O or S, preferably O; and X is NR11, where R11 is hydrogen, C
1-6
alkyl, C
6-10
aryl, C
7-12
arylalkyl, C
1-6
alkoxy, C
6-10
aryloxy, hydroxy, C
1-6
alkanoyl or C
1-6
carboxyalkyl. In a subgroup of these group of compounds and pharmaceutically acceptable salts and esters thereof, R3 is hydrogen, C
1-6
alkyl, C
6-10
aryl, or C
7-12
arylalkyl, preferably C
1-6
alkyl, most preferably methyl. In a family of these subgroups of compounds and pharmaceutically acceptable salts and esters thereof, A is preferably straight-chain or branched C
1-4
alkylene.
In another preferred class of compounds and pharmaceutically acceptable sal
Haikala Heimo
Kaheinen Petri
Kaivola Juha
Karjalainen Arto
Levijoki Jouko
Jones Dwayne C.
Orion Corporation
Sterne, Kessler, Coldstein & Fox P.L.L.C.
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