3-Thia-4-arylquinolin-2-one derivatives as smooth muscle relaxants

#Potassium channels are transmembrane proteins which are ubiquitously expressed in mammalian cells and represent one of the largest and the most diverse group of ion channels from a molecular perspective. Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are largely regulated by voltage, cell metabolism, calcium and receptor mediated processes. [Cook, N. S., Trends in Pharmacol. Sciences 1988, 9, 21; and Quast, U., et al., Trends in Pharmacol. Sciences 1989, 10, 431]. Calcium-activated potassium (KCa) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of Kca channels is regulated by intracellular [Ca2+], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K+ solutions, KCa channels are divided into three subclasses: large conductance (BK or Maxi-K) are those having a conductance of greater than about 150 picosemens (pS); intermediate conductance are those having a conductance of about 50–150 pS; and small conductance are those having a conductance of less than about 50 pS. Large-conductance calcium-activated potassium channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. et al., Pflugers Archiv. 1987, 408, 98; Baro, I., et al., Pflugers Archiv. 1989, 414 (Suppl. 1), S168; and Ahmed, F. et al., Br. J. Pharmacol. 1984, 83, 227].

#Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and maintain the transmembrane voltage near the K+ equilibrium potential (Ek) of about −90 millivolts (mV). It has been shown that opening of potassium channels shift the cell membrane potential towards the Ek, resulting in hyperpolarization of the cell. [Cook, N. S., Trends in Pharmacol. Sciences 1988, 9, 21]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. Those BK channels which are regulated by both voltage and intracellular Ca2+ act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of BK channels may result in protection of neuronal cells, as well as other types of cells, e.g., cardiac cells. [Xu, W., Liu, Y., Wang, S., McDonald, T., Van Eyk, J. E., Sidor, A., and O'Rourke, B. Cytoprotective Role of Ca2+-activated K+ Channels in the Cardiac Inner Mitochondrial Membrane. Science 2002, 298, 1029–1033].

#BK channels have been shown to be one of two physiologically relevant potassium channels in relaxing human smooth muscle, including both intestinal and penile smooth muscle. Evidence that relaxation of smooth muscle is beneficial to irritible bowel syndrome and erectile dysfunction has been reported. See the following references: Christ, G. J. Drug News Perspect. 2000, 13, 28–36; Poynard T. et al. Alimentary Pharmacology and Therapeutics 2001, 15, 355–361; and Argentieri, T. M. U.S. patent application Ser. No. 2002/0183395.

#The present invention describes novel 3-thia-4-arylquinolin-2-one compounds and related derivatives of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein: R and R1 are independently hydrogen or methyl; R2, R3, and R4 are independently hydrogen, halogen, cyano, nitro, or trifluoromethyl, provided R2, R3, and R4 are not all hydrogen; R5 is bromo, chloro, or nitro; R6 and R7 are independently hydrogen, C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —CH2C3-7 cycloalkyl, —(CH2)1-3OH, —(CH2)2-3NR8R9, —(CH2)1-3CN, or —(CH2)1-3Ar, where Ar is selected from the group consisting of phenyl, naphthyl, furanyl, thienyl, and pyridyl, and Ar is unsubstituted or substituted with 1–2 methoxy substituents; or NR6R7 taken together form or NR6R7 taken together are selected from the group consisting of R8 and R9 are independently hydrogen or C1-6alkyl; R10 is a bond, O, S, NR11, or CHR12; R11 is hydrogen, C1-6 alkyl, CHO, C(O)Me, —(CH2)2-3OH, —CH2CH2OCH2CH2OH, —C(O)furanyl, or —CH2CH═CHPh; R12 is hydrogen, hydroxy, C1-6 alkyl, —CH2Ph, —C(O)OR8, —(CH2)NR8R9, or 1-piperidinyl; and m is 0, 1, 2, or 3.

#The present invention also provides a method for the treatment or alleviation of disorders associated with BK channels, such as ischemia, stroke, convulsions, epilepsy, asthma, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction, urinary incontinence and especially male erectile dysfunction and irritable bowel syndrome which comprises administering together with a conventional adjuvant, carrier or dilutent a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

#The term “atropisomer” refers to a stereoisomer resulting from restricted rotation about a single bond where the rotation barrier is high enough to permit isolation of the isomeric species.