Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-29
2003-01-14
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S370400
Reexamination Certificate
active
06506784
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of substituted 1-arylpyrazole sulfonate compounds, their synthesis and their use as pest GABA receptor inhibitors and pesticides.
2. Related Art
&ggr;-Aminobutyric acid (GABA) receptors are intrinsic membrane glycoproteins in vertebrate and invertebrate neuronal tissues that are members of the ligand-gated ion channel superfamily of receptors. GABA receptors play a major role in the inhibition of central nervous system (CNS) neuronal activity due to the widespread distribution of GABA-releasing and GABA-receptive neurons.
Vertebrate GABA receptors can be divided into two major classes: the GABA
A
and GABA
C
subtypes, and GABA
B
receptor subtype, which are distinguished by differences in their effector mechanisms and pharmacology (Knapp, R. J., et al.,
Neurochem. Res.
15:105-112 (1990)). GABA
A
and GABA
C
receptors are transmitter-operated chloride channels that are activated by GABA to open their chloride channel while GABA
B
receptors are thought to mediate changes in cyclic AMP levels through the activation of phospholipase activity (Eldefrawi, A. T. and Eldefrawi, M. E.,
FASEB J.
1:262-271 (1987); Knapp, R. J., et al.,
Neurochem. Res.
15:105-112 (1990)). The GABA
A
receptor and its associated chloride ion channel make up the so-called GABA
A
receptor-channel complex.
GABA is the endogenous ligand for the GABA
A
receptor of the GABA
A
-complex, and is the major inhibitory neurotransmitter in the vertebrate brain, in the insect CNS and at insect neuromuscular junctions (Enna et al., In: Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties, Alan R. Liss, Inc., New York, pp. 41-56 (1986); Sattelle, D. B.,
Adv. Insect Physiol.
22:1-113 (1990)). GABA binding to its receptor stimulates chloride ion conductance through the associated chloride ion channel to inhibit synaptic transmission (Knapp, R. J., et al.,
Neurochem. Res.
15:105-112 (1990); U.S. Pat. No. 5,487,976). When two molecules of GABA bind at sites on the receptor, the chloride channel undergoes a conformational change and opens, allowing chloride ions to flow passively down the electrochemical gradient into the neuron. An influx of chloride into the cell causes a change in the membrane potential, usually a hyperpolarization, which results in an inhibition of the nerve impulse. Blockage of the GABA-gated chloride channel reduces neuronal inhibition, which leads to hyper-excitation of the CNS, resulting in convulsions and death. In contrast, irreversible or hyperactivation of the channel suppresses neuronal activity, resulting in ataxia, paralysis, coma and death (Bloomquist, J. R.,
Comp. Biochem. Physiol.
106C:301-314 (1993)).
GABA
A
receptors belong to the class 1 family of neurotransmitter/hormone receptors. Other class 1 members include the glycine receptor, the serotonin type-3 receptor, the nicotinic acetylcholine receptors (muscle and neuronal types) and several excitatory amino acid receptors of vertebrates. Class 1 receptors employ no second messengers and are found where a fast conductance is required. In contrast to class 1 receptors, class 2 receptors (e.g. muscarinic, adrenergic, and others) are coupled to a second messenger and/or a G protein for their transduction, with the channel involved being separate (and usually distant) from the receptor, which is both an agonist-binding and G protein-binding molecule (Barnard, E. A., et al.,
TiNS
10:502-509 (1987)).
GABA
A
receptors are pentameric oligomers, of about 250 kilodaltons (kDa), composed of six different types of subunits, &agr;, &bgr;, &ggr;, &dgr;, &egr; and &rgr;, each of approximately 50 kDa (Olsen, R. W., and Tobin, A. J.,
FASEB J.
4:1469-1480 (1990); Hevers, W., and Lüddens, H.,
Mol. Neurobiol.
18:35-86 (1998)). Each subunit comprises a large extracellular N-terminal domain that putatively includes the ligand-binding site, four hydrophobic presumed membrane-spanning domains, one or more of which contribute to the wall of the ion channel, and a small extracellular C-terminus (Lüddens, H., and Wisden, W.,
TiPS
12:49-51 (1991); Olsen, R. W., and Tobin, A. J.,
FASEB J.
4:1469-1480 (1990); Hevers, W., and Lüddens, H.,
Mol. Neurobiol.
18:35-86 (1998)). Heterologous expression in vitro of different combinations of GABA receptor subunit types (&agr;, &bgr;, &ggr;, &dgr; etc.) and subunit isoforms (&agr;1, &agr;2, etc. except &dgr;) results in heteromultimeric receptors with differing structure and pharmacology (Schofield, P. R.,
TiPS
10:476-478 (1989); Burt et al.,
FASEB J.
5:2916-2923 (1991)).
GABA receptors also play an important role in the chemical control of pests, particularly insects, such as fleas, ticks, house flies, fruit flies, plant bugs, boll weevils, grasshoppers, cockroaches, mosquitoes, beetles, locust and moths (Hainzl, D., et al.,
Chem. Res. Toxicol.
11:1529-1535 (1998)). To date, all insect GABA receptors studied gate a fast acting chloride ion conductance. Although they appear to share many of the properties of GABA
A
-type receptors in the vertebrate CNS, the majority of receptors in the insect nervous system appear to be bicuculline-, pitrazepin- and RU5135-insensitive (Anthony, N. M., et al., Comp.
Mol. Neurobiol.,
Pichon, Y., ed., Birkhäuser Verlag, Basel, Switzerland, pp. 172-209 (1993); Wafford, K. A., et al.,
J. Neurochem.
48:177-180 (1987)). These findings indicate that insect GABA receptors contain several drug binding sites with structural and target site specificities that are different from vertebrate receptor-binding sites (Hainzl, D., et al.,
Chem. Res. Toxicol.
11:1529-1535 (1998)). Selective insecticides, e.g. insecticides with favorable selective toxicity for insects relative to vertebrates, are based in part on this target-site specificity between the GABA receptors of insects and the GABA
A
receptors of vertebrates (Moffat, A. S.,
Science
261:550-551 (1993); Hainzl, D., et al.,
Chem. Res. Toxicol.
11:1529-1535 (1998)).
Radiolabeled ligand binding studies have considerably expanded our knowledge of insect GABA receptor pharmacology. Within the insect GABA receptor three distinct binding sites have been identified: the GABA receptor agonist binding site, a benzodiazepine binding site and a convulsant binding site (Lummis, S. C. R.,
Comp. Biochem. Physiol.
95C:1-8 (1990); Rauh, J. J., et al.,
TiPS
11:325-329 (1990)). The convulsant binding site of GABA receptors in pests is the major target site for many of the drugs and pesticides currently on the market.
Convulsant drugs and pesticides act at the GABA receptor in pest brain, ganglia and muscle as noncompetitive blockers. Inhibition of GABA receptors in pests produces neurotoxicity (e.g. convulsions, paralysis, coma and death). In the early 1980s, the pesticides lindane and cyclodienes (e.g. dieldrin) were shown to antagonize the action of GABA in stimulating chloride uptake by various pest nerve and muscle preparations (Narahashi, T., Pharmacol. Toxicol. 78:1-14 (1996)). GABA receptors in pests are also blocked by picrotoxin, phenylpyrazole pesticides (e.g. Fipronil®), bicyclophosphorous esters (e.g. &tgr;-butylbicyclophosphoronthionate), and bicycloorthobenzoates (4-n-propyl-4′-ethynylbicycloorthobenzoate) (U.S. Pat. No. 5,853,002). These pesticides block transmission of signals by GABA, and are very effective on a wide range of economically important pests.
Unfortunately, many potent pesticides and their derivatives also act at the GABA
A
receptors of animals. For example, fipronil sulfone and desulfinyl fipronil, a metabolite and photoproduct of fipronil, respectively, are not only toxic to pests, but also to upland game birds, freshwater fish and invertebrates, and waterfowl. In addition, fipronil itself is a toxicant for mammals even without oxidation to the sulfone (Hainzl, D., et al.,
Chem. Res. Toxicol.
11:1529-1535 (1998)).
Pesticides that effectively kill pests but that have little toxicity for animals and humans remain the aim of current research efforts. The present
Agrafiotis Dimitris
Dhanoa Daljit S.
Doller Dario
Meegalla Sanath
Seward R. Lee
3-Dimensional Pharmaceuticals Inc.
Ramsuer Robert W.
Sterne Kessler Goldstein & Fox P.L.L.C.
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