Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-19
2002-01-22
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S450000, C514S453000, C514S454000, C514S464000, C514S338000, C514S321000, C514S254110, C514S236800, C514S617000, C544S148000, C544S378000, C546S197000, C546S283700, C548S526000, C549S432000, C549S433000, C549S441000, C549S358000, C549S359000, C564S172000
Reexamination Certificate
active
06340704
ABSTRACT:
This application is the National Stage of International Patent Application Ser. No. PCT/JP98/01871, filed Apr. 23, 1998.
TECHNICAL FIELD
The present invention relates to amide derivatives exhibiting excellent cell differentiation-inducing actions or cell differentiation-inducing action-enhancing actions such as bone morphogenetic protein (BMP) action or BMP-enhancing action or neurotrophic factor (NTF) actions (e.g., nerve growth factor (NGF) action, brain-derived neurotrophic factor (BDNF) action, neurotrophin-3 (NT-3) action and glial cell line-derived neurotrophic factor (GDNF) action) or NTF-enhancing action, a method of their production and a pharmaceutical composition containing them.
BACKGROUND ART
Bone morphogenetic protein (BMP), isolated from demineralized bone, is the only group of protein factors known to be capable of ectopic bone induction. It is therefore useful as an osteogenesis promoter in bone fracture healing, bone reconstruction etc. (A. E. Wang, Trends in Biotechnology, Vol. 11, pp. 379-383 (1993)).
To date, a number of such substances with BMP action-enhancing activity have been reported, i.e., retinoic acid, vitamin D3, estrogen and glucocorticoid (V. Rosen & R. S. Thies, Trends in Genetics, Vol. 8, pp. 97-102 (1992); Y. Takuwa et al., Biochemical and Biophysical Research Communications, Vol. 174, pp. 96-101 (1991)).
Also, because BMP directly promotes osteoblast differentiation, it is assumed to play a role as a coupling factor in bone remodelling, and is thought to be closely involved in bone metabolism. Also, it has been reported that the BMP content in bone substrate in aged animals has been considerably decreased (M. L. Urist, Bone and Mineral Research, Vol. 6 (ed. by W. A. Peck), pp. 57-112, Elsevier, 1989), suggesting that BMP is profoundly involved in the maintenance of bone mass. This suggests that BMP is promising as a therapeutic drug for various bone diseases such as osteoporosis. However, because BMP is normally present in trace amounts in living body so that its supply is limited, and because BMP is a protein so that a problem arises in its administration, the target diseases to which it is applicable are limited.
In addition, BMP has been reported to possess an activity like that of neurotrophic factors (V. M. Paralkar et al., Journal of Cell Biology, Vol. 119, pp. 1,721-1,728 (1992)). Also, it is known that the BMP gene is strongly expressed in brain tissue (E. Ozkaynak et al., Biochemical and Biophysical Research Communications, Vol. 179, pp. 116-123 (1991)). Also, BMP has been suggested as playing an important role in neural tube formation in embryogenesis (K. Basler et al., Cell. Vol. 73, pp. 687-702 (1993)).
Neurotrophic factors, a group of proteinous factors playing an important role in the survival and functional expression of neurons, include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF). NGF promotes the differentiation and maturation of the sympathetic ganglion cells and dorsal root ganglion cells of the neural tube in the peripheral nervous system (A. M. Davies & R. M. Lindsay, Developmental Biology, Vol. 111, pp. 62-72 (1985); R. Levi-Montalcini, EMBO Journal, Vol. 6, pp. 1,145-1,154 (1987)), and acts on the cholinergic neurons of septa (procephalic basal ganglia) in the central nervous system (H. Gnahn et al., Developmental Brain Research, Vol. 9, pp. 45-52 (1983); H. Hatanaka & H. Tsukui, Developmental Brain research, Vol. 30, pp. 47-56 (1986); F. Hefti, Journal of Neuroscience, Vol. 6, pp. 2,155-2,162 (1986)). NGF is essential for the maintenance of nervous function even after completion of neuron differentiation. BDNF acts on the dorsal spinal root ganglion cells and nodal ganglion cells in the peripheral nervous system but does not act on sympathetic ganglion cells (R. M. Lindsay & H. Rohrer, Developmental Biology, Vol. 112, pp. 30-48 (1985); R. M. Lindsay et al., Developmental Biology, Vol. 112, pp. 319-328(1985); A. M. Davies et al., Journal of Neuroscience, Vol. 6, pp. 1,897-1,904 (1986)). On the other hand, in the central nervous system, BDNF acts on the cholinergic neurons and GABA (&ggr;-aminobutyric acid)-acting neurons of septa, and the dopaminergic neurons of the mesencephalon (R. F. Alderson et al., Neuron, Vol. 5, pp. 297-306 (1990); C. Hyman et al., Nature, Vol. 350, pp. 230-232 (1991); B. Knusel et al., Proceedings of the National Academy of Sciences of the United States of America, Vol. 88, pp. 961-965 (1991)). NT-3 is characterized by potent action on the sensory neurons derived from the neural plate, although its action overlaps those of NGF and BDNF in the peripheral nervous system (P. Ernfors et al., Proc. Natl. Acad. Sci. USA, Vol. 87, pp. 5,454-5,458 (1990); A. Rosenthal et al., Neuron, Vol. 4, pp. 767-773 (1990)). However, there are no known neurons of the central nervous system that respond to NT-3.
As a substance exhibiting NGF action, sabeluzole [4-(2-benzothiazolylmethylamino)-&agr;(p-fluorophenoxy)methyl]-1-(piperidine) ethanol] has been reported (New Current, Vol. 4, No. 26, p. 14 (1993)]; in addition, SR57746A [Neuroscience, Vol. 55, p. 629 (1993)), T-588 (Japanese Patent Unexamined Publication No. 95070/1992) and MS430 (Journal of University of Occupational and Environmental Health, Vol. 17, p. 131 (1995)) have also been reported to enhance NGF action. Also, as compounds exhibiting NGF secretion-inducing action, steroids, catechols and cytokines have been reported (Experimental Neurology, Vol. 124, pp. 36-42 (1993)).
Alzheimer dementia has been characterized by extensive lesion and exfoliation of cerebrial cortical neurons, as well as degeneration and exfoliation of cholinergic neurons of the basal ganglia, including the septal area; NGF and new neurotrophic factors are considered as candidates for therapeutic drugs therefor (F. Hefti & W. J. Weiner, Annual Neurology, Vol. 20, pp. 275-281 (1986)). Because these neurothrophic factors are proteins, however, their application are subject to limitation.
Also, low-molecular compounds known to promote osteoblast proliferation and differentiation include, for example, ipriflavone (K. Notoya et al., Journal of Bone and Mineral Research, Vol. 9, pp. 395-400 (1994)) and vitamin K2 (Y. Akedo et al., Biochemical and Biophysical Research, Vol. 187, pp. 814-820 (1992)) but these do not possess ectopic bone induction capability as does BMP.
Compounds known to exhibit actions like those of neurotrophic factors, such as the extension of neurites and neuron survival, include lactastatin (S. Omura et al., Journal of Antibiotics, Vol. 40, pp. 113-117 (1991)), retinoic acid (M. Minana et al., Proceedings of the National Academy of Science of the USA, Vol. 876, pp. 4335-4339 (1990)), staurosporin (T. B. Shea et al. Journal of Neuroscience Research, Vol. 33, pp. 398-407 (1990)), K252a (G. D. Borasio et al., Neuroscience Letters, Vol. 108, pp. 207-212 (1990)), and MS818 (A. Awaya et al., Biological and Pharmaceutical Bulletin, Vol. 16, pp. 248-253 (1993)).
(1) A naphthalenecarboxamide represented by the formula:
wherein Ar
1
represents allylene-(R
8
)
2
(R
8
: a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy etc.); Ar
2
represents aryl-(R
9
)
2
(R
9
: a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy etc.); R
1
represents a hydrogen atom, lower alkyl, hydroxy or lower alkoxy; R
2
represents a hydrogen atoms, lower alkyl or a group which forms ═O in cooperation with R
1
; R
3
represents a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy or the like; R
4
represents a hydrogen atom or lower alkyl; R
7
represents a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy or the like; each of R
10
and R
11
represents a hydrogen atom, halogen, lower alkyl, hydroxy, a lower alkoxy, CON(R
16
)
2
(R
16
represents a hydrogen atom, lower alkyl or OR
13
(R
13
is a hydrogen atom or lower alkyl)) or the like; is disclosed in U.S. Pat. No. 5,308,852;
(2) a compound represented by the formula:
wherein R
Hazama Masatoshi
Kato Koki
Marui Shogo
Notoya Kohei
Chao Mark
Huang Evelyn Mei
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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