Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-25
2003-02-25
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217000, C514S297000, C514S311000, C514S513000, C514S535000, C514S569000, C514S640000
Reexamination Certificate
active
06525043
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the use of a particular class of chemical compounds as modulators of SK
Ca
, IK
Ca
and BK
Ca
channels, and to pharmaceutical compositions comprising the SK/IK/BK channel modulating agents.
BACKGROUND ART
Ion channels are transmembrane proteins, which catalyse the transport of inorganic ions across cell membranes. The ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, secretion of hormones, contraction of muscles, etc.
Many drugs exert their effects via modulation of ion channels. Examples are anti-epileptic compounds like Phenytoin and Lamotrigine, which block voltage dependent Na
+
-channels in the brain, anti-hypertensive drugs like Nifedipine and Diltiazem, which block voltage dependent Ca
2+
-channels in smooth muscle cells, and stimulators of insulin release like Glibenclamide and Tolbutamide, which block an ATP-regulated K
+
-channel in the pancreas.
All mammalian cells express potassium (K
+
) channels in their cell membranes, and the channels play a dominant role in the regulation of the membrane potential. In nerve and muscle cells they regulate the frequency and form of the action potential, the release of neurotransmitters, and the degree of broncho- and vasodilation.
From a molecular point of view, the K
+
channels represent the largest and most diverse group of ion channels. For an overview they can be divided into five large subfamilies: Voltage-activated K
+
channels (K
v
), long QT related K
+
channels (KvLQT), inward rectifiers (K
IR
), two-pore K
+
channels (K
TP
), and calcium-activated K
+
channels (K
Ca
).
The latter group, the Ca
2+
-activated K
+
channels, consists of three well-defined subtypes: SK channels, IK channels and BK channels. SK, IK and BK refer to the single-channel conductance (Small, Intermediate and Big conductance K channel). The SK, IK, and BK channels exhibit differences in e.g. voltage- and calcium-sensitivity, pharmacology, distribution and function.
Ca
2+
-activated SK channels are present in many central neurons and ganglia, where their primary function is to hyperpolarize nerve cells following one or several action potentials to prevent long trains of epileptogenic activity to occur. The SK channels are also present in several peripheral cells including skeletal muscle, gland cells, liver cells, and T-lymphocytes.
The significance of SK channels in normal skeletal muscle is not clear, but their number is significantly increased in denervated muscle, and the large number of SK channels in the muscle of patients with myotonic muscle dystrophia suggest a role in the pathogenesis of the disease.
A number of blockers of SK channels exist, e.g. apamin, atracurium, pancuronium, and tubocurarine, and they are all positively charged molecules which act as pore blockers.
The Ca
2+
-activated IK channel shares a number of characteristics with the Ca
2+
-activated SK channel, since it is highly K-selective, is activated by sub-micromolar concentrations of Ca
2+
, and has an inwardly rectifying conductance. However, there are also striking differences. The unit conductance of the IK channel is 4-5 fold higher than that of the SK channel, and the distribution of the IK channel is restricted to the blood and vasculature. Thus, the IK channel is not expressed in the nervous system and in muscle, but in endothelial cells, cells of epithelial origin and in red blood cells.
In the red blood cells, where the IK channel has been denominated the Gardos channel, a rise in the concentration of intracellular Ca
2+
opens the channel and causes potassium loss and cell dehydration, a condition which is exacerbated in sickle cell anemia. Promising therapeutic approaches for sickle cell anemia involve specific block of the IK channel.
IK channels have also been implicated in the microvasculature of the kidney, where they may be responsible for the vasodilatory effects of bradykinin. The decrease in blood pressure during septic shock is caused by an increased NO production by the endothelial cells, and the IK channels in these cells are responsible for maintaining the Ca
2+
influx activating the Ca
2+
-sensitive NO-synthase.
In brain capillary endothelial cells, IK channels, activated by endothelin that is produced by neurons and glia, shunt excess K
+
into the blood. Neurotrophilic granulocytes, i.e. mobile phagocytic cells that defend the body against microbial invaders, undergo large depolarisation subsequent to agonistic stimulation, and IK channels have been implicated in depolarising the stimulated granulocyte.
The Ca
2+
-activated BK channels present in many cells including most central and peripheral nerve cells, striated muscle cells, cardiac cells, smooth muscle cells of the airways, the vasculature, the gastrointestinal tract and bladder, in endo- and exocrine glands including pancreatic b-cells and in kidney tubules.
SUMMARY OF THE INVENTION
According to the present invention it has now been found that a particular group of chemical compounds possess valuable activity as modulators of SK
Ca
, IK
Ca
and/or BK
Ca
channels.
In its first aspect the invention relates to the use of chemical compounds represented by the general Formulas I-XI
or a pharmaceutically acceptable salt or an oxide or a hydrate thereof,
wherein R represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, acyl, acyl-alkyl, alkoxy-alkyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, phenyl-alkyl, alkoxy-phenyl, or alkoxy-phenyl-alkyl; and
A′ and A″ independently of each another, represent hydrogen or alkyl, or together with the carbon atoms to which they are attached form a benzene ring;
X and Y, independently of each another, represent
hydrogen, halogen, trihalogenmethyl, alkyl, alkenyl, alkynyl, amino, nitro, cyano, or amido, or a group of the formula —R′, —OR′, —SR′, —R′OR″, —R′SR″, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, or —C(S)SR′;
wherein R′ and R″, independently of each another, represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or alkoxy, or a group of the formula NR′″R″″, wherein R′″ and R″″, independently of each another, represent hydrogen or alkyl;
for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of SK
Ca
, IK
Ca
and/or BK channels.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.
DETAILED DISCLOSURE OF THE INVENTION
According to the present invention it has now been found that a particular group of chemical compounds possess valuable activity as modulators of SK
Ca
, IK
Ca
and/or BK
Ca
channels.
SK/IK/BK Modulating Agents
In the context of this invention, chemical compounds capable of affecting SK
Ca
, IK
Ca
and/or BK
Ca
channels are designated SK/IK/BK channel modulating agents. The SK/IK/BK channel modulating agents for use according to the invention may affect the ion channels by opening (activating) the channels or by inhibiting (blocking) the channels.
The SK/IK/BK channel modulating agents for use according to the invention show activity in concentrations below 100 &mgr;M, preferably below 10 &mgr;M, more preferred below 1 &mgr;m. In its most preferred embodiment the SK/IK/BK channel modulating agents for use according to the invention show activity in low micromolar and the nanomolar range.
In a preferred embodiment, the SK/IK/BK channel modulating agent for use according to the invention is a carbazole derivative represented by the general Formula I
or a pharmaceutically acceptable salt or an oxide or a hydrate thereof,
wherein,
V represents —CH
2
— or —CH═CH—; and
Z represents
wherein R represents hydrogen, alk
Christophersen Palle
Jensen Bo Skaaning
Olesen Soren Peter
Strobaek Dorte
Teuber Lene
Birch & Stewart Kolasch & Birch, LLP
NeuroSearch A/S
Reamer James H.
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