Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-10-30
2000-02-29
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514217, 5142328, 514287, 514290, 514410, 514411, 540521, 540522, 544125, 544126, 546 65, 546110, 548421, 548423, 548450, 548451, A61K 31365, A61K 3140, C07D21724, C07D31748
Patent
active
060309679
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/97/02858, filed Aug. 19, 1997.
TECHNICAL FIELD
This invention relates to fused cyclic compounds having very satisfactory bone morphogenetic protein (BMP) like and/or neurotrophic factor [for example, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell line-derived neurotrophic factor (GDNF)]-like activity or enhancing activity of BMP and/or neurotrophic factor activity, to a technology for producing the compound, and to relevant pharmaceutical compositions.
BACKGROUND ART
Bone morphogenetic proteins (BMPs) are the family of proteins isolated from demineralized bone and known to be able to induce ectopic bone formation. As such, BMP is of value as a bone formation promoting agent for bone fracture healing and bone remodeling [A. E. Wang, Trends Biotechnol., 11, 379-383, 1993].
Furthermore, since it directly promotes osteoblast differentiation, BMP is supposed to be playing the role of a coupling factor in bone remodeling and is, therefore, considered to be closely associated with bone metabolism. It has also been reported that the BMP content of bone matrix in aged animals has been considerably depressed [M. L. Urist, Bone and Mineral Research, 6 (ed by W. A. Peck), 57-112, Elsevier, 1989], indicating that BMP is closely related to the maintenance of bone mass. This finding suggests that BMP may be a promising drug for the treatment of various diseases of bone, such as osteoporosis. However, BMP usually exists only in trace amounts in the organisms, and sources of its supply were limited. Moreover, as it is a protein, the routes of administration are restricted, and therefore the spectrum of diseases which can be treated is quite limited.
It has also been reported that BMP has neurotrophic factor-like activity [V. M. Paralkar et al., J. Cell Biol., 119, 1721-1728, 1992]. Also known is an intense expression of the BMP gene in the brain tissue [E. Ozkaynak et al., Biochem. Biophys. Res. Commun., 179, 116-123, 1991]. It has also been suggested that BMP is playing an important role in the formation of the neural tube during embryonic development [K. Basler et al., Cell, 73, 687-702, 1993]. It is, therefore, believed that BMP is closely involved in the differentiation or functional maintenance of nerve cells.
Neurotrophic factor (NTF) is a family of proteins playing important roles in the maintenance of neuron and functional expression of neurons and includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell line-derived neurotrophin factor (GDNF), among others. NGF in the peripheral nervous system promotes the differentiation and maturation of the neural crest sympathetic ganglion and dorsal root ganglion cells [A. M. Davies & R. M. Lindsay, Dev. Biol., 111, 62-72, 1985; R. Levi-Montalcini, EMBO J., 6, 1145-1154, 1987] and in the central nervous system acts on the cholinergic neurons of septa (forebrain basal ganglia) [H. Gnahn et al, Dev. Brain Res., 9, 45-52, 1983; H. Hatanaka & H. Tsukui, Dev. Brain Res., 30, 47-56, 1986; F. Hefti, J. Neurosci., 6, 2155-2162, 1986]. NGF is necessary for the maintenance of nerve function even after completion of differentiation of neurons. BDNF in the peripheral nervous system acts on the dorsal root ganglion and nodular ganglion cells but does not act on sympathetic ganglion cells [R. M. Lindsay & H. Rohrer, Dev. Biol., 112, 30-48, 1985; R. M. Lindsay et al., Dev. Biol., 112, 319-328, 1985; A. M. Davies et al., J. Neurosci., 6, 1897-1904, 1986]. In the central nervous system, BDNF acts on the cholinergic neurons and GABA (.gamma.-aminobutyric acid)-nergic neurons of septa and the dopaminergic neurons of midbrain [R. F. Alderson et al., Neuron, 5, 297-306, 1990; C. Hyman et al., Nature, 350, 230-232, 1991; B. Knusel et al., Proc. Natl. Acad. Sci. USA, 88, 961-965, 1991]. The activites of NT-3 on the peripheral nervous system are similar to that of NGF and BDNF, however NT-3 characteristically acts strongly on neural placodes-de
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Hazama Masatoshi
Marui Shogo
Notoya Kohei
Ogino Masaki
Raymond Richard L.
Takeda Chemical Industries Ltd.
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