This invention relates to novel potassium channel agonists useful to treat diseases or disorders associated with potassium channels. The invention also relates to chemical intermediates useful in the synthesis of potassium channel agonists.
The art reveals that a compound of structural formula (I): ##STR2## wherein R is hydrogen or an acyl group has been isolated from the fungal organism Gliocladium virens IFO9166. Watanabe et al. Journal of Natural Products 53, 5, 1176-1181 (1990), and was disclosed as useful as a possible antifungal or antimicrobial agent. The compound wherein R is hydrogen is known in the art as CAF-603 and is hereinafter referred to as Compound B, and was referred to by Wantanbe as CAF-603. The present invention, on the other hand, presents novel compounds useful as a potassium channel agonists.
Potassium channel agonists are useful for a number of physiological disorders in mammals, including humans. Ion channels, including potassium channels, are found in all mammalian cells and are involved in the modulation of various physiological processes and normal cellular ionic homeostasis. Potassium ions generally control the resting potential of cell membranes and the efflux of potassium ions causes repolarization of the plasma membrane after cell depolarization. Potassium channel agonists hyperpolarize the cell and diminish electrical excitability. There are a number of different potassium channel subtypes and one of the most important physiologically is the high conductance Ca.sup.2+ -activated K.sup.+ (Maxi-K) channel which is present in neuronal tissue and smooth muscle. Intracellular calcium concentration (Ca.sup.2+ i) and membrane potential gate these channels. For example, Maxi-K channels are opened by increases in intracellular calcium ion concentration or membrane depolarization. Elevation of intracellular calcium concentration is required for neurotransmitter release and for smooth muscle contraction. Therefore, modulation of Maxi-K channel activity affects transmitter release from the nerve terminal and the contractability of various smooth muscle tissues. The compounds of this invention are therefore useful in the treatment of neurological disorders in which hyperpolarization of neuronal cells elicits anticonvulsive and antiischemic effects. They are also useful to hyperpolarize and relax smooth muscles including, but not exclusively, those in the vasculature and airways to elicit antihypertensive and antiasthmatic actions, respectively. As smooth muscle relaxants, potassium channel agonists are useful in a variety of pathophysiological conditions that include: (1) relieving muscle cramps associated with dysmenorrhea; (2) treatment of urinary incontinence; (3) treatment of irritable bowel syndrome; and (4) treatment of angina.
A number of drugs in development function as potassium channel agonists. Examples of these include the structural classes represented by the cromakalim and pinacidil type potassium channel openers. These potassium channel agonists exert their effects primarily by opening ATP-dependent K.sup.+ channels. They have demonstrated vasodilatory activity due to their activation of these channels in vascular smooth muscle cells. Furthermore, they also activate ATP-dependent K.sup.+ channels in tracheal smooth muscle suggesting a possible utility as antiasthmatic drugs. These compounds have either weak effects or no effects on Maxi-K channels. The present invention represents the first sesquiterpene which is useful as a potassium channel agonist. The present invention relates to novel carotane sesquiterpenes which are useful as potassium channel agonists. Because these compounds target the Maxi-K channel, they have utility in suppressing neurotransmitter release, as well as in relaxing vascular and airways smooth muscle.