Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-05-15
2002-10-01
Siegel, Alan (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S523000, C514S524000, C514S620000, C514S618000, C514S617000, C514S563000, C514S562000, C514S561000, C514S534000
Reexamination Certificate
active
06458846
ABSTRACT:
TECHNICAL FIELD
The present invention relates to ion channel modulating agents. More particularly, the present invention relates to a particular class of chemical compounds that has proven useful as modulators of SK
Ca
, IK
Ca
and BK
Ca
channels. In further aspects, the present invention relates to the use of these SK/IK/BK channel modulating agents for the manufacture of medicaments, and pharmaceutical compositions comprising the SK/IK/BK channel modulating agents.
The SK/IK/BK channel modulating agents of the invention are useful for the treatment or alleviation of diseases and conditions associated with the SK/IK/BK channels.
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 endotheliai 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 oxime derivatives possess valuable activity as modulators of SK
Ca
, IK
Ca
and/or BK
Ca
channels.
In its first aspect the invention relates to novel oxime derivatives represented by the general formula
wherein
R
1
represents hydrogen; an alkyl group; a cycloalkyl group; hydroxy; an alkoxy group; an acyl group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO
2
, —CN, —CF
3
, alkyl, cycloalkyl, hydroxy, and alkoxy; a group of the formula —CH
2
CN; a group of the formula —CH
2
CO
2
R′, wherein R′ represents hydrogen or an alkyl group; a group of the formula —CH
2
CONR
IV
R
V
, wherein R
IV
and R
V
independently represents hydrogen or an alkyl group; or a group of the formula —CH
2
C(═NOH)NH
2
;
R
2
represents hydrogen, an alkyl group, a cycloalkyl group, a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO
2
, —CN, —CF
3
, alkyl, cycloalkyl, hydroxy, and alkoxy;
X represents oxygen, sulphur, or an amino group, preferably an amino group of the formula NHR
3
;
R
3
represents hydrogen, an alkyl group, a cycloalkyl group, a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO
2
, —CN, —CF
3
, alkyl, cycloalkyl, hydroxy, and alkoxy; and
R
4
and R
5
, independently of each another represents hydrogen; halogen; —NO
2
; —CN; —CF
3
; an alkyl group; an alkoxy group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO
2
, —CN, —CF
3
, alkyl, cycloalkyl, hydroxy, and alkoxy; or a group of the formula —SO
2
NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group;
or R
4
and R
5
together form an additional 4 to 7 membered fused ring, which fused ring may be aromatic or partially saturated, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, —NO
2
, —CN, —CF
3
, and a group of the formula —SO
2
NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group.
In a second aspect, the invention provides a pharmaceutical composition comprising a therapeutically-effective amount of an oxime derivative of the invention, or a pharmaceut
Christophersen Palle
Jensen Bo Skaaning
Strobaek Dorte
Teuber Lene
Birch Stewart Kolasch & Birch, LLP.
Neurosearch A/S
Siegel Alan
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