Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1998-05-28
1999-09-28
Mach, D. Margaret M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
544353, 546102, 546118, 546171, 546172, 546178, C07D40100, C07D24136, C07D21900, C07D21538
Patent
active
059591072
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to new isoquinoline derivatives and their pharmaceutically acceptable acid addition salts. The derivatives of the present invention have inhibitory activity on neuronal cell death (apoptotic cell death-type) caused by excessive apoptosis in a nervous system and they are useful for prevention or treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis, cerebral ischemic injury such as stroke, and peripheral neuropathy in diabets mellitus.
BACKGROUND ART
Cell death is classified from morphological change into necrosis that whole cells are swelled by cell membrane degeneration and die out, and apoptosis that whole cells reduce the sizes to change the nuclear structure and to fragmentize DNA into ladders and die out (Kerr and Harrnon, Apoptosis: The molecular Basis of Cell Death, Tomei and Cope (Eds), pp5-29 (1991), Cold Spring Harbor Laboratory Press). It has become clear that the apoptosis is greatly involved in pathology suffering from many diseases, and there is possibility of new treatment by controlling inappropriate apoptosis (Thompson, Science, Vol. 267, pp 1456-1462 (1995)).
Several lines of evidence suggest that neuronal cell death in neuro degenerative disorders occurs by apoptosis (Alzheimer disease, Parkinson disease, Huntington chorea, amyotrophic lateral sclerosis and the like) (Su et al., Neuro Report, Vol. 5, pp 2529-2533 (1994); Yoshiyama et al., Acta Neuropathologica, Vol. 88, pp 207-211 (1994); Lassman et al., Acta Neuropathologica, Vol. 89, pp 35-41 (1995); Smale et al., Experimental Neurology, Vol. 133, pp 225-230 (1995); Dragunow et al., Neuro Report, Vol. 6, pp 1053-1057 (1995); Portera-Cailliau et al., Journal of Neuroscience, Vol. 15, pp 3775-3787 (1995); Cotman and Anderson, Molecular Neurobiology, Vol. 10, pp 19-45 (1995); Bredesen, Annals of Neurology, Vol. 38, pp 839-851 (1995)). In addition, apoptosis has been suggested to play a role in delayed neuronal death of Mongolian gerbil following transitant ischemia (Nitatori et al., Journal of Neuroscience, Vol. 15, pp 1001-1011 (1995)). As some agents for inhibiting neuronal apoptotic cell death, protein and RNA synthesis inhibitors can be exemplified. However, specificity of these inhibitors for advanced drug development is questionable. Further, a product of Bcl-2 gene and a protein factor such as a neurotropic factor have problems because these are not safely and effectively administered in vivo, so that these are not practically used. Therefore, therapeutic method for the control of neuronal cell death in neurodegenerative disorders has not been established. Hitherto, many isoquinoline derivatives are known, especially, a compound binding an alkyl group via an sulfur atom at a 5-position of isoquinoline (Euerby, Mervin R. and Waigh, Roger D., J. Chem. Soc. Chem. Commun., Vol. 2, 127-128 (1984)). However, a compound binding an aromatic ring via a sulfur atom at a 5-position of isoquinoline has not been known.
DISCLOSURE OF INVENTION
In view of the above-mentioned conditions, the present inventors have been earnestly studied and found new compounds having excellent effects for suppression of the neuronal cell death caused by excess apoptosis in a nervous system. Accordingly, the present invention aims to provide new isoquinoline derivatives having inhibition activity for the nervous cell death caused by apoptosis acceleration in a nervous system.
The present invention relates to new isoquinoline derivatives and their pharmaceutically acceptable acid addition salts there of.
The new isoquinoline derivatives and their pharmaceutically acceptable acid addition salts there of are represented by the following general formula (I). ##STR2## wherein Ar shows an aromatic ring or a heterocycle, n shows 0, 1 or 2, and R.sup.1 shows a substituted group selected from hydrogen, nitro and amino.
Preferably, Ar of the above isoquinoline derivatives is selected from following aromatic ring: ##STR3## wherein R.s
REFERENCES:
Chemical Abstracts 121:187302, Ikegaki, 1994.
Chemical Abstracts 120:144163, Desantis, 1993.
Chemical Abstracts 119:49246, Peglion, 1993.
Chemical Abstracts 118:100528, Kajiwara, 1992.
Chemical Abstracts 117:226338, Berliner, 1992.
Chemical Abstracts 116:120903, Buxbaum, 1991.
Ishiguro Susumu
Ogane Nobuo
Okue Masayuki
Saitou Yasunari
Seya Motohide
M. Mach D. Margaret
Snow Brand Milk Products Co. Ltd.
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