Preparation of 3-substituted-4-arylquinolin-2-one derivatives

Details Preparation of 3-substituted-4-arylquinolin-2-one derivatives Preparation of 3-substituted-4-arylquinolin-2-one derivatives

2000-11-28

2002-03-05

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S488000, C549S489000, C546S157000

Reexamination Certificate

active

06353119

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides a novel process for the preparation of 3-substituted-4-arylquinolin-2-one derivatives which are modulators of the large-conductance calcium-activated potassium (BK) channels and, therefore, useful in the protection of neuronal cells and diseases arising from dysfunction of cellular membrane polarization and conductance. The present invention also provides novel intermediates for the preparation thereof.
BACKGROUND OF THE INVENTION
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 (K
Ca
) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of K
ca
channels is regulated by intracellular [Ca
2+
], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K
+
solutions, K
Ca
channels are divided into three subclasses: large conductance (BK)>150 pS; intermediate conductance 50-150 pS; small conductance<50 pS. Large-conductance calcium-activated potassium (Maxi-K or BK) 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 (E
k
) of about −90 mV. It has been shown that opening of potassium channels shift the cell membrane potential towards the equilibrium potassium membrane potential (E
k
), 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. BK channels which are regulated by both voltage and intracellular Ca
2+
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.
A range of synthetic and naturally occurring compounds with BK opening activity have been reported. The avena pyrone extracted from avena sativa-common oats has been identified as a BK channel opener using lipid bi-layer technique [International Patent application WO 93/08800, published May 13, 1993]. In U.S. Pat. No. 5,200,422, issued Apr. 6, 1993 to Olesen, et al., a number of benzimidazole derivatives were disclosed as openers of BK channels by using single-channel and whole-cell patch-clamp experiments in aortic smooth muscle cells. Further work was reported by Olesen, et al., in
European J. Pharmacol.,
251, 53-59 (1994).
Sit, et al., in U.S. Pat. No. 5,892,045, issued Apr. 6,1999, disclosed a series of 4-aryl-3-hydroxyquinolin-2-one derivatives, while Hewawasam, et al., in U.S. Pat. No. 5,972,961, issued Oct. 26, 1999, disclosed a series of 4-aryl-3-aminoquinolini-2-one derivatives which are openers of BK channels and useful in the treatment of disorders sensitive to potassium channel opening activity.
E. S. Hamanaka in U.S. Pat. No. 5,565,472, issued Oct. 15, 1996, discloses a number of 4-aryl-3-(heteroarylureido)-1,2-dihydro-2-oxo-quinoline derivatives which are inhibitors of acyl coenzyme A; cholesterol acyltransferase and are useful as hypolipidemic and antiatherosclerosis agents.
It is the object of the present invention to provide a useful, convenient and improved process for the preparation of certain 3-substituted-4-arylquinolin-2-one derivatives which are openers of the high-conductance calcium-activated potassium (BK) channels and the utility thereof is more fully described by Hewawasam, et al. in U.S. provisional application No. 60/111,079 filed Dec. 4, 1998.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of 3-substituted-4-arylquinolin-2-one derivatives having the general formula
wherein R, R
1
, R
2
, R
3
and R
4
are as defined below and which are openers of the large conductance calcium-activated K
+
channels also known as Maxi-K or BK channels useful for the treatment of disorders sensitive to potassium channel opening activity such as ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction and urinary incontinence. More specifically, the present invention provides a unique process starting from a substituted coumarin and using a photochemical cyclization method.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for the preparation of 3-substituted-4-arylquinolin-2-one derivatives which are modulators of the large-conductance calcium-activated potassium (BK) channels and have the general formula
wherein R is hydrogen or methyl; R
1
is bromo, chloro or nitro; and R
2
, R
3
and R
4
each are independently hydrogen, halogen, nitro or trifluoromethyl, provided R
2
, R
3
, and R
4
are not all hydrogen; or a nontoxic pharmaceutically acceptable salt thereof.
The present invention also provides useful intermediates of Formula VI
and to a process for the preparation thereof wherein R is hydrogen or methyl; R
1
is bromo, chloro or nitro; and R
2
, R
3
and R
4
each are independently hydrogen, halogen, nitro or trifluoromethyl, provided R
2
, R
3
and R
4
are not all hydrogen.
The term “nontoxic pharmaceutically acceptable salt” as used herein and in the claims is intended to include nontoxic base addition salts with inorganic bases. Suitable inorganic bases such as alkali and alkaline earth metal bases include metallic cations such as sodium, potassium, magnesium, calcium and the like. Unless otherwise specified, the term “halogen” as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine while the term “halide” is intended to include bromide, chloride and iodide anion.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms including hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. The products may be true solvates, while in other cases, the products may merely retain adventitious solvent or be a mixture of solvate plus some adventitious solvent. It should be appreciated by those skilled in the art that solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of Formula I can exist in two tautameric forms. It should be appreciated by those skilled in the art that the quinoline ring can exist in an enol form. It is intended that both enolic tautomers of the compounds of Formula I are included within the scope of the present invention.
The following Reaction Scheme illustrates representative general procedures for the preparation of intermediates and methods for the preparation of compounds of formula I according to this invention. It should also be evident to those skilled in the art that appropriate substitution of both the materials and methods disclosed herein will produce the examples illustrated below and those encompassed by the scope of this invention.
(a) LiHMDS/THF, −78° C. to RT
(b) 12N HCl
(c) pTSA, Toluene, reflux
(d) LiHMDS
(e) (CH
3
O)
2
SO
2
, K
2
CO
3
(f) hv, MeOH
The preparation of compounds of Formula I is advantageously carried out by the reactions illustrated in Reaction Scheme 1. The coumarin compound of Formula III is preferably prepared by condensing &ggr;-butyrolact

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