Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-01
2002-11-12
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S414000, C514S416000, C514S469000, C549S469000, C549S491000, C548S454000
Reexamination Certificate
active
06479536
ABSTRACT:
This application is a 371 of PCT/JP99/06764 filed Dec. 2, 1999.
TECHNICAL FIELD
The present invention relates to novel benzofuran derivatives, their production, and pharmaceutical compositions containing them. More specifically, it relates to compounds having excellent pharmacological activities such as a neurotrophic factor-like activity, a neurotrophic factor activity-enhancing activity, a neurodegeneration inhibitory activity, a &bgr;-amyloid toxicity inhibitory activity and the like, and are effective as prophylactic and therapeutic drugs for neurodegenerative diseases and the like.
BACKGROUND ART
Neurodegenerative diseases are progressive diseases to cause destructive injuries such as the nerve cell death. As principal neurodegenerative diseases, there have been known central nervous diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Hantington's disease, and the like and peripheral neuropathies such as typically diabetic neuropathy. Many of them relate to aging and, in fact, the onset increases with aging, whereas there is a case in which the onset begins even at a middle age and further at a younger age.
As a result of studies on the structure and function of brains, the roles of neurotransmitters and neurotrophic factors and so on have been gradually elucidated, but many parts of the causes of neurodegeneration are still unknown. Only for Parkinson's disease, the relation between it and a specific neurotransmitter, namely dopamine, has been clarified, whereby L-dopa that is the precursor of dopamine has been used as a drug for reducing the nervous symptoms and for recovering the function. However, L-dopa does not suppress the progress of neurodegeneration, and the effect of L-dopa is gradually lost with a progress of the disease condition, namely the degeneration and deficiency of dopamine-based nerve cells. Also, Alzheimer's disease is a disease that is caused by the degeneration and deficiency of a variety of nerve cells such as acetylcholine-based nerve cells, monoamine-based nerve cells, and the like and, as for the drugs therefor, cholinesterase inhibitors have been marketed or under development. Nevertheless, like L-dopa for Parkinson's disease, they are still within the region of symptomatic therapy to improve the nerve symptoms temporarily.
Thus, there has not been reported up to the present time any drug that protects nerve cells from the toxicity of factors causing cell death thereby suppressing the progress of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
Moreover, it is said that the cell death in neurodegenerative diseases is caused by the toxicity of the factors that are intrinsic to the respective diseases and, for example, in Alzheimer's disease, the endogenous &bgr;-amyloid is considered to be a factor to cause the cell death. &bgr;-Amyloid is a protein constituting the senile plaque, which is a neuropathological characteristic to be seen in brain of a patient suffering from Alzheimer's disease, and is composed of 40 to 43 amino acids. It has been elucidated that the addition of this &bgr;-amyloid to a primary culture of hippocampus nerve cell causes nerve cell death [Science, Vol. 245, pp. 417-420 (1989)] and, also, it has been shown that the coagulation of &bgr;-amyloid is indispensable for the expression of its toxicity and the like [Neurobiology of Aging, Vol. 13, pp. 587-590 (1992) and Journal of Molecular Biology, Vol. 218, pp. 149-163 (1991)]. For toxicity expression mechanism of &bgr;-amyloid, there have been conceived that 1) &bgr;-amyloid forms an ion channel to allow an inflow of calcium ions, 2) &bgr;-amyloid accelerates generation of free radicals, 3) &bgr;-amyloid activates tau protein kinase I (TPK-I) to promote the phosphorylation of tau, 4) &bgr;-amyloid activates the microglia, from which the neurotoxin is secreted, and the like.
Recently, it has been elucidated that neurotrophic factors such as IGF-1 (insulin-like growth factor), NGF (nerve growth factor), and the like inhibit the apoptosis of nerve cells by &bgr;-amyloid and the like, and that, as the mechanism thereof, inhibition of TPK-I/GSK-3&bgr; (glycogen synthetase kinase 3) by activation of PI-3 kinase is concerned in the apoptosis inhibition [Journal of Neuroscience (J. Neurosci.), Vol. 11, pp. 2552-2563 (1991), Science, Vol. 267, pp. 2003-2005 (1995), and The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 272, 154-161 (1997)]. When PI-3 kinase is inhibited by &bgr;-amyloid and TPK-I/GSK-3&bgr; is activated, pyruvate dehydrogenase (PDH) is inhibited, thereby affecting the synthetic reaction system of acetylcholine to lower the content of acetylcholine. This fact agrees with an observation that the content of acetylcholine is lowered in brain of a patient suffering from Alzheimer's disease. On the contrary, it is expected that the activation of PI-3 kinase results in not only the prevention of nerve cell death but also an increase in the content of acetylcholine in brain, thereby improving the nerve symptoms. In addition, it can be expected that inhibition of TPK-I/GSK-3&bgr; increases the intracerebral glucose utilization, which is lowered in Alzheimer's disease [The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 269, 3568-3573 (1994) and Endocrinology, Vol. 125, pp. 314-320 (1989)].
Further, the following compounds have been reported as compounds having a fused nitrogen-containing heterocyclic group on benzene ring that is fuzed with furan ring or dihydrofuran ring.
1) As compounds having an inhibitory activity of bone resorption and bone metabolism, compounds that are represented by the formula:
wherein R
1
is hydrogen, lower alkyl, acyl, amino, acylamino, nitro, halogen or hydroxy-lower alkyl that may have one or more appropriate substituents;
R
2
is hydrogen, lower alkyl, acyl, lower alkoxy, acyl-lower alkyl, aryl, cyano, mono- (or di- or tri-) halo-lower alkyl, lower alkylthio or hydroxy-lower alkyl that may have one or more appropriate substituents;
R
3
is hydrogen, lower alkyl, lower alkenyl, cyclo lower alkyl-lower alkyl, halogen, acyl, acyl-lower alkyl, acylamino, acylamino-lower alkyl, acyl-lower alkenyl, acyloxy-lower alkyl, acyl-lower alkylthio-lower alkyl, amino-lower alkyl, mono- (or di-) lower alkylamino, lower alkylthio-lower alkyl, hydroxyimino-lower alkyl that may have one or more appropriate substituents, hydroxy-lower alkyl that may have one or more appropriate substituents, hydroxy-lower alkylthio-lower alkyl, cyano-lower alkyl, mono- (or di-) lower alkoxyower alkyl that may have one or more appropriate substituents, lower alkyl substituted with aryl that may have one or more appropriate substituents, mono- (or di-) lower alkylamino-lower alkyl, lower alkyl substituted with a heterocyclic group that may have one or more appropriate substituents, a heterocyclic group that may have one or more appropriate substituents, heterocyclic thio, heterocyclic thio-lower alkyl, heterocyclic oxy, heterocyclic oxy-lower alkyl, heterocyclic aminoimino-lower alkyl, aryl, amino or nitro;
R
2
and R
3
may be combined each other to form a group of
(1) lower alkylene that may have one or more appropriate substituents,
(2) lower alkenylene that may have one or more appropriate substituents, or
(3) the formula: —(A
1
)
m
—W—(A
2
)
n
—, wherein each of A
1
and A
2
is lower alkylene that may have one or more appropriate substituents or lower alkenylene that may have one or more appropriate substituents, W is —S—, —S(O)— or —N(R
5
)— (wherein R
5
is hydrogen, lower alkyl or acyl), and each of m and n is an integer of 0 or 1;
X is O or S, Y is vinylene or a group represented by the formula: —NHCO—, —NHSO
2
—, —OCO—, —OCH
2
—, —NHCOCO—, —NHCOCH═CH—, —NHCOCH
2
—, —NHCONH— or —N(R
6
)CO— (wherein R
6
is lower alkyl); Z is a heterocyclic group that may have one or more appropriate substituents or aryl that may have one or more appropriate substituents; 1 is an integer of 0 or
Arikawa Yasuyoshi
Kato Kouki
Ohkawa Shigenori
Okura Masahiro
Setoh Masaki
Patel Sudhaker B.
Rao Deepak R.
Takeda Chemical Industries Ltd.
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