Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-20
2003-05-20
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S082000, C546S272700, C546S321000
Reexamination Certificate
active
06566359
ABSTRACT:
This invention pertains to a series of new derivatives of 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, their synthesis, and the use of these compounds as platelet-activating factor antagonists, inhibitors of certain protein kinases, transcriptional inhibitors of COX-2 expression, and as agents effective in protecting brain tissue from injuries related to trauma or disease.
Various derivatives of 1,4 dihydropyridines have been described with properties that include one or more of the following: platelet activating factor antagonist activity, coronary vessel dilators, antihypertensives, antiischemic, antithrombotic activity, cerebral vessel dilators, peripheral vessel dilators, renal vessel dilators. See U.S. Pat. Nos. 5,177,211; 5,070,205; 5,068,337; 4,937,242; 4,801,598; 4,788,205; 4,755,512; 3,996,234; and 3,974,274. See also, WO 90/12015 and EPO 0325 187.
It has been known for sometime that brain ischemia promotes the accumulation of arachidonic acid. See N. G. Bazan, “Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain,” Biochim. Biophys. Acta, vol. 218, pp. 1-10 (1970); N. G. Bazan, “Changes in free fatty acids of brain by drug induced convulsions, electroshock and anesthesia,” J. Neurochem., vol. 18, pp. 1379-1385 (1971). In addition, newborn mammals and adult poikilotherms, unlike adult rodents and nonhuman primates, do not display an arachidonic acid accumulation induced by ischemia. See Bazan 1971; N. G. Bazan et al., “Regional distribution and rate of production of free fatty acids in rat brain,” J. Neurochem., vol. 18, pp.1387-1393 (1971); and M. I. Aveldano et al., “Differential lipid deacylation during brain ischemia in a homeotherm and a poikilotherm. Content and composition of free fatty acids and triacylglycerols,” Brain Res., vol.100, pp. 99-110 (1975). A connection has been suggested between brain damage and both the accumulation of arachidonic acid and the activation of phospholipase A
2
, because resistance to brain damage was shown in animals that do not accumulate arachidonic acid (e.g., newborn mammals and mature poikilotherms) but not in animals that accumulate arachidonic acid (e.g., adult mammals). This pattern of resistance to brain damage was shown in animal models subjected to ischemia, stroke, cerebral edema, and epilepsy. See N. G. Bazan et al., “Membrane lipids in the pathogenesis of brain edema: Phospholipids and arachidonic acid, the earliest membrane components changed at the onset of ischemia,” In: Advances in Neurology, Vol 28: Brain Edema. (J. Cervós-Navarro and R. Ferszt, eds), Raven Press, New York, pp 197-205 (1980); N. G. Bazan et al., “Endogenous pools of arachidonic acid enriched membrane lipids in cryogenic brain edema,” In: Recent Progress in the Study of Brain Edema, (K. G. Go and A. Baethmann, eds), Plenum Press, New York, pp 203-212 (1984); and N. G. Bazan et al., “Free arachidonic acid and membrane lipids in the central nervous system during bicuculline induced status epilepticus,” In: Advances in Neurology Vol 34: Status Epilepticus, (A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, R. J. Porter, eds), Raven Press, New York, pp 305-310 (1983).
Phospholipase A
2
generates the platelet-activating factor (“PAF”) precursor as well as arachidonic acid. Platelet-activating factor (PAF) accumulation has been shown to participate in ischemia-reperfusion brain damage and excitotoxic neuronal injury. See N. G. Bazan, “Inflammation: A signal terminator,” Nature, vol. 374, pp.501-502 (1995); N. G. Bazan et al., “Platelet-activating factor is both a modulator of synaptic function and a mediator of cerebral injury and inflammation,” In: Advances in Neurology, Vol. 71 :Cellular and Molecular Mechanisms of Ischemic Brain Damage, (B. Siesjö and T. Wieloch, eds.), Lippincott-Raven Publishers, Philadelphia, vol. 37, pp. 475-484 (1996b); N. G. Bazan et al., “Platelet-activating factor and other bioactive lipids,” In: Cerebrovascular Disease, Pathophysiology, Diagnosis and Management (M. D. Ginsberg and J. Bogousslavsky, eds.) Chapter 37, Blackwell Science Publishers, Malden, Mass., pp. 532-555 (1998); N. G. Bazan et al., “Membrane-derived lipid second messengers as targets for neuroprotection: Platelet-activating factor,” In: Emerging Strategies in Neuroprotection, Advances in Neuroprotection (P. J. Marangos and H. Lal, eds.), Birkhäuser, Boston, pp. 238-251 (1992); T. Panetta et al., “Effects of a platelet-activating factor antagonist (BN 52021) on free fatty acids, diacylglycerols, polyphospho-inositides and blood now in the gerbil brain: Inhibition of ischemia reperfusion induced cerebral injury,” Biochem. Biophys. Res. Comm., vol.149, pp.580-587 (1987); K. Nishida et al., “Platelet-activating factor in brain regions after transient ischemia in gerbils,” Stroke, vol. 27, pp.514-519 (1996); S. A. L. Bennett et al, “Platelet-activating factor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity,” Cell Death Differentiation, vol. 5, pp. 867-875 (1998); H. Bito et al., “Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons,” Neuron, vol.9, pp. 285-294 (1992); B. Bonavida et al., “Platelet-activating factor and the cytokine network in inflammatory processes,” Clin. Rev. Allergy, vol. 12, pp. 381-395 (1994); G. Feurstein et al., “Platelet-activating factor: a putative mediator in central nervous system injury?,” Stroke, vol. 21(suppl III), pp. III-90-III-94 (1990); and H. A. Gelbard et al., “Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin,” J. Virol., vol. 68, pp. 4628-4635 (1994).
PAF, a potent phospholipid messenger, is released during ischemic insults to the brain and after seizures. See R. Kumar et al., “Production and effects of platelet-activating factor in the rat brain,” Biochem. Biophys. Acta, vol. 963, pp.375-383 (1988). Multiple receptors and multiple functions for PAF has been reported. There are seven transmembrane-spanning domain receptors as well as intracellular binding sites for PAF. See Z. Honda et al., “Transfected platelet-activating factor receptor activates mitogen-activated protein (MAP) kinase and MAP kinases kinases in Chinese hamster ovary cells,” J. Biol. Chem., vol. 269, pp.2307-2315 (1994); V. L. Marcheselli et al., “Distinct platelet-activating factor binding sites in synaptic endings and in intracellular membranes of rat cerebral cortex,” J. Biol. Chem., vol. 265, pp. 9140-9145 (1990); and V. L. Marcheselli et al., “Platelet-activating factor is a messenger in the electroconvulsive shock-induced transcriptional activation of c-fos and zif-268 in hippocampus,” J. Neurosci. Res., vol.37, pp. 54-61, (1994). PAF enhances glutamate release at the presynaptic level, which is antagonized by the plasma membrane-type receptor inhibitor BN-52021. See G. D. Clark et al., “Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor,” Neuron, vol.9, pp. 1211-1216 (1992); N. G. Bazan et al., “Platelet activating factor in the modulation of excitatory amino acid neurotransmitter release and of gene expression,” J. Lipid Mediat. Cell Signal, vol. 14, pp.321-330 (1996a); and C. Chen et al., “Attenuated long-term potentiation in hippocampal dentate gyrus neurons of mice deficient in the platelet-activating factor receptor,” J. Neurophysiol., vol. 85, pp. 384-390 (2001).
PAF is also a retrograde messenger of long-term synaptic potentiation. See K. Kato et al., “Platelet activating factor as a potential retrograde messenger in Cal hippocampal long-term potentiation,” Nature, vol. 367, pp. 175-179 (1994). Moreover, PAF is a transcriptional activator, and this action is blocked by the intracellular PAF antagonist LAU-8080 (BN-50730). See V. L. Marcheselli et al., 1994; V. L. Marcheselli et al., “Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus: Inhibition by a platelet-activating factor antagonist,” J. Biol. Chem., vol. 271, pp. 24794-24799 (1996); Bazan et al.,
Bazan Nicholas G.
Builla-G. Julio
Marcheselli Victor L.
Sunkel Carlos
Board of Supervisors of Louisiana State University and Agricultu
Davis Bonnie J.
Runnels John H.
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