Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-04-08
1994-08-16
Chang, Celia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514318, 514321, 546193, 546197, 546226, A61K 31445, C07D21112, C07D40702
Patent
active
053387457
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to amide derivatives of dihydrocaffeic acid and their application to pharmaceutical uses. More specifically, the present invention relates to amide derivatives of dihydrocaffeic acid which are capable of inducing production and secretion of a nerve growth factor (hereinafter referred to as NGF) in specific tissues in the brain and to pharmaceutical agents containing these derivatives as effective constituents for the prevention of the progression of degenerative diseases in the central nervous system and the therapeutic treatment thereof.
2. Description of the Prior Art
With extended average life expectancy, rapid progress in research has been made all over the world in order to establish methods for early diagnosis, ethiological study and therapeutic treatment of various gerontological diseases; degenerative diseases in the central nervous system are a major object of this research. In particular, senile dementia of Alzheimer type (hereinafter abbreviated to as SDAT), a typical disease of such diseases, is now becoming a big social problem because the number of the cases is markedly increasing, mainly in developed countries, and the patients suffer through a miserable progressive course. Although many researchers and clinicians have been intensively studying the pathology of this disease, particularly in recent years, the fundamental cause of the disease has not been elucidated and therefore no effective methods for the early diagnosis and treatment of the disease have been established.
However, a number of pathological observations demonstrates that the direct causes of the early characteristic symptoms of SDAT, such as memory failure and disorientation, are the progressive changes in large cell cholinergic nerve fibers which project into the memory and learning centers, i.e., the cerebral cortex and hippocampus, from the cerebral basal ganglia and dysfunctions in said controlled areas caused by this change. In fact, a few case reports showed that the symptoms were slightly improved by administering an acetylcholine biosynthesis precursor or a cholinesterase inhibitor as an activator to SDAT patients in order to activate the cholinergic system in the brain. However, in general, the observed effects were not so significant as expected.
Since discovery of NGF by R. Levi-Monterlcini, S. Cohen and others, considerable research on NGF has been carried out. To date, it has been proved by physiological experiments that NGF is an essential factor for differentiation and growth of sensory and sympathetic nerve cells in the peripheral nervous system, particularly in the embryonal period, and further for the survival of the sympathetic nerve cells and maintenance of their functions in the maturation period.
However, because NGF is a physiologically active substance which exists only in an extremely small quantity, accurate knowledge regarding distribution and movement of NGF in tissues, which directly demonstrates the action of NGF in the body, has not been attained in spite of intensive research for a long period of time. Only recently, a highly sensitive enzyme-linked immunosorbent assay (hereinafter referred to as ELISA) for an active subunit of NGF (beta-NGF, hereinafter simply designated as NGF) was developed and improved with sufficient sensitivity and specificity to study the matters described above (S. Furukawa et al.: J. Neurochem., 40, 734-744, 1983 and S. Korshing and H. Thoenen: Proc. Natl. Acad. Sci., USA, 80, 3513-3516, 1983).
Furthermore, the NGF gene was cloned and its structure was analyzed, which makes it possible to establish a method for the quantitative measurement of its messenger RNA (hereinafter abbreviated as mRNA) by using the complementary DNA (hereinafter abbreviated as cDNA) of beta-NGF (D. L. Shelton and L. F. Reichardt: Proc. Natl. Acad. Sci., USA, 81, 7951-7955, 1984 and R. Heumann et al.: EMBO J., 3, 3183-3189, 1984).
Then, using the techniques described above, it was proved that there is a positive
REFERENCES:
Junard et al. "Long-term administration of mouse nerve growth faith to adult rats" CA 114:115710w (1990).
Fukazawa et al. "Preparation of catechol derivatives" CA 112(15) 138764q (1990).
Koul et al. "Synergists for pyrethrum" CA 92:123386n (1980).
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Chemical Abstracts, vol. 92, No. 15, Apr. 1980 Columbus, Ohio, Abstract No. 123386n "Synergists for Pyrethrum . . . Acids" p. 215.
Chemical Absracts, vol. 105, No. 23, Dec. 1986 Columubs, Ohio, U.S. Abstract No. 202725n "Chemical Structure-Biological Activity . . . Analogs IV" p. 14.
Journal of the Chemical Society, Perkin Transactions 1 No. 6, (1983), Letchworth GB pp. 1219-1221 Sondengam et al. "Convenient Reduction . . . Couple".
Tetrahedron Letters No. 10, Mar. 1976, Oxford GB pp. 763-766 Umino et al. "Sodium Acyloxyborohydride as new Reducing Agents . . . Amines".
Journal of Chromatographic Science vol. 29, No. 6, Jun. 1991 pp. 267-271 Noggle et al. "Gas Chromatographic and Mass . . . Sassafras Oil".
Furukawa et al., FEBS 4216, vol. 208, No. 2 (Nov. 1986) "Aliphatic side chain of catecholamine potentiates the stimulatory effect of the catechol part on the synthesis of nerve growth factor" pp. 258-262.
Fukazawa Nobuyuki
Iizuka Hajime
Miyama Yukio
Yano Osamu
Chang Celia
Mitsui Toatsu Chemicals, Incorporation
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