Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1996-07-23
2001-03-13
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S557000, C554S225000, C562S493000, C562S503000, C562S512000, C562S581000, C562S588000, C562S606000
Reexamination Certificate
active
06201021
ABSTRACT:
SUMMARY
This invention is related to pentanoic acid derivatives. More particularly, this invention is related to:
(1) pentanoic acid derivatives of the formula (1):
wherein all the symbols are the same meaning as hereafter defined, and non-toxic salts thereof and acid addition salts thereof,
(2) improving agent of the brain functions containing pentanoic acid derivatives of the formula (I) and non-toxic salts thereof and acid addition salts thereof as active ingredient,
(3) process for the preparation of pentanoic acid derivatives of the formula (I) and non-toxic salts thereof and acid addition salts thereof and
(4) improving agent of the brain functions containing pentanoic acid derivatives of the formula (X):
wherein all the symbols are the same meaning as hereafter defined, and non-toxic salts thereof and acid addition salts thereof as active ingredient.
BACKGROUND
The two major structural units that form the brain are neuron and glia. The neuron is composed of a cell body with dendrites. Ramified structures that transmit neuro-information along an axon and those receiving impulses via other neurons are the two types of dendrites known in existence. Neuro-information is conducted from one neuron to another via transmission across the synapse, a cleft that closely connects the dendrites of two communicating neurons.
However, glia is units that complement the functions of these neurons by supplying nutrients, eliminating catabolites/wastes, maintaining a proper ion equilibrium and performing other related functional roles for neurons to physiologically function normally. The glia encompass various types of cells. There are astrocytes, oligodendrocytes and microglia in the central nervous system; Schwann's and mantle cells in the peripheral nervous system; and ependymal cells in the ventricular endothelium.
The growth and differentiation of neurons prevail immediately before and after birth, whereas those of glia persist even after birth. The etiological factors of neurodegenerative diseases (such as Alzheimer's disease, multiple sclerosis, hepatic encephalopathy and delayed neuronal death) have been thought to be attributed mainly to abnormalities in the neurons. However, attention has recently been focused on the functional abnormalities of glia surrounding the neurons, especially astrocytes (Scientific American, pp45-52, April 1989). This is because astrocytes not only act as complementary cells, but they also promote the metabolism of glutamate and &ggr;-amino butyrate (GABA), syntheses of neuropeptides and cytokines, and function as either immunocysts or neurons beside displaying important roles in regulating brain functions. As such, abnormalities in the astrocyte functions may be the determinant factors in inducing various brain-related diseases.
When encephalopathia occurred, reactive astrocytosis generated from astrocyte-derived reactive astrocytes agglutinate in the vicinity of sites where neurons die [J. Anat., 106, 471 (1970); Dev. Biol., 72, 381 (1979); Adv. Cell. Neurobiol., 2, 249 (1981)]. Although reactive astrocytosis eventuated in brain insults has been thought to be a compensatory response to neuronal regeneration, recent evidences have suggested that the excessive response of reactive astrocytosis triggers neurodegenerative decidua [Science, 237, 642 (1987); Brain Res., 481, 191 (1989); Ibid, 547, 223 (1991)]. From the participating reactive astrocytes in this excessive response, various neurotransmitters and cytokines are released [Cytobios., 61, 133 (1990)]. Of these, the most significant have been the identification of nerve growth factor (NGF) [Biochem. Biophys. Res. Commun., 136, 57 (1986); Brain Res., 560, 76 (1991)] and &bgr;-amyloid precursor protein (&bgr;-APP) secretions [Neuron., 3, 275 (1988); J. Neurosci. Res., 25, 431 (1990); FEBS Lett., 292, 171 (1991)]. The expression of &bgr;-APP has prompted reactive astrocytes as a possible source of &bgr;-amyloid, and the close relationship between &bgr;-amyloid deposits and reactive astrocytosis has since been implicated [J. Neurol. Sci., 112, 68 (1992)]. &bgr;-amyloid plagues display an important role in the induction of Alzheimer's disease (AD), a representative neurodegenerative disease [Proc. Natl. Acad. Sci. USA., 82, 4245 (1985); Brain Res. Reviews, 16, 83 (1991); TIPS, 12, 383 (1991)].
Based on the dose/efficacy relationship, NGF secreted from the reactive astrocytes elicits a neurotoxic activity 1.0×10
5
-fold more potent than that of &bgr;-amyloid alone [Science, 250, 279 (1990)], and indicates a synergistic effect on &bgr;-amyloid-induced neuronal death [Proc. Natl. Acad. Sci. USA, 87, 9020 (1990)]. Furthermore &bgr;-amyloid also facilitates neuronal deaths induced by excitatory amino acids such as glutamate and N-methyl-D-aspartate (NMDA) [Brain Res., 533, 315 (1990)]. As such, these facts may be able to account for the pathological findings related to &bgr;-amyloid in AD.
Recent findings have implicated that abnormalities in the astrocyte functions are found in AD patients. In addition, reactive astrocytes have been postulated to relate directly to AD induction [Neurol., 40, 33 (1990) Neurobiol. Aging, 13, 239 (1992)].
However, it is still unclear as to why reactive astrocytosis would occur superfluously. The present inventors therefore studied the inductions of reactive astrocytes so as to define the physiological functions of this endogenous element using primary cultured astrocytes from neonatal rat brains. By culturing astrocytes from physically destroyed brains by normal culture procedure, the reactive astrocytes were successfully induced. Consequently, in addition to a remarkably abnormal cell proliferation initiated on 5 days in vitro (DIV), enhanced glial fibrillary acidic protein (GFAP) contents and specific morphological changes (hyperplasia) in the reactive astrocytes were also observed.
After establishing and confirming the above findings, the functional changes which occurred during the induction of reactive astrocytes were pursued. The results did not revealed any significant changes in the voltage-dependent calcium, sodium and potassium channels and glutamate receptor responses in reactive astrocytes. However, a disappearance of GABA
A
receptor responses as inhibitory regulation was accompanied by the attenuated abnormal proliferation of astrocytes in cultures. The response decreased to such an extent that the astrocyte growth was rendered undetectable. Based on the observation that no receptor responses to glycine (an inhibitory amino acid) were elicited, reactive astrocytes were probably induced by a decrease in the inhibitory control of astrocytes.
All in all, when encephalopathy occurred, a disappearance of GABA
A
receptor responses of astrocytes ensued. Because astrocytes persisted abnormally, atypical levels of neurotransmitters and cytokines (especially NGF and &bgr;-APP) were released. These extraordinary events then produced synergistic effects that eventually induced abnormal ramifications/extension of neuronal dendrites followed by neuronal death. In other words, sideration of neurodegenerative diseases ensued.
Hence, treatment and/or prevention of neurodegenerative diseases attributed to functional abnormalities can be innovated and designed by improving the GABA
A
receptor responses of reactive astrocytes.
Furthermore, excessive glutamate and aspartate released at the terminals of ischemic neurons in brain insults cause persistent depolarization that eventually neutralizes the neurons concerned [Nikkei Sci. J., 9, 52 (1991)]. This event is then followed by excessive brain edema and encephalophyma (or astrocytosis), which in turn is ensued by death. As neurotoxic activities induced by the excessive response of reactive astrocytes are suppressed, GABA
A
receptor responses of astrocytes are improved. These events thus reduce not only the ischemia-induced mortality cases but can also alleviate/treat the post-ischemia brain
Kishimoto Kazuo
Ohno Hiroyuki
Ohuchida Shuichi
Tateishi Narito
Ono Pharmaceutical Co. Ltd.
Stockton Laura L.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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