Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Patent
1999-09-13
2000-12-05
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
514665, 544 54, 548182, 560302, A61K 31325, C07D27734, C07D27736, C07D27906
Patent
active
061567949
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Thiamine deficiency has long been known to cause neurological disorders, such as Wernicke-Koraskoff syndrome or cerebral beriberi. Many of the symptoms of Wernicke-Korsakoff syndrome parallel those of Alzheimer's disease, in particular with respect to loss of memory, mental confusion and dementia. The gene for early-onset familial Alzheimer's disease has recently been identified to be coincident with the position (14q24.3) of the gene encoding the human E2k component (dihydrolipoyl succinyl transferase) of the .alpha.-ketoglutarate dehydrogenase (KDH) complex, a thiamine pyrophosphate-dependent enzyme system (Ali et al., 1994; Nakano et al., 1994). This chromosomal position is also associated with another inherited neurological disorder, Machado-Joseph disease. The neurological damage associated with thiamine deficiency is thought to be due to an increase in extracellular glutamate levels during periods of KDH depression (Hazell et al., 1993; Heroux & Butterworth, 1995). Furthermore, glutamate toxicity is believed to be involved in many neurodegenerative diseases, e.g., Alzheimer's disease, parkinsonism, stroke, and epilepsy, as well as hypertension, hypoglycemia and mental disorders such as schizophrenia.
Considerable effort has been devoted to discovery of glutamate antagonists (B. Scatton, Life Sciences, 55, 2115-2124 (1994); S. A. Lipton et al., N. Engl. J. Med., 330, 613-622 (1994)) in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders (R. J. Thomas, J. Am. Geriatr. Soc., 43 1279-1289 (1995)). Unfortunately, while known antagonists can provide neuroprotection, excessive action of these classical blocking agents can obtain undesirable side effects (Scatton, supra; Lipton et al. (1994), supra). To minimize these undesirable side effects, modification of the redox modulatory sulfhydryl groups of the glutamate receptor has been suggested as a possibly superior therapeutic strategy (H. Gozlan et al., TiPS, 16, 368-374 (1995)). Unlike classical antagonists that can give complete inhibition by interaction at the glutamate receptor (e.g., CGS 19755) or directly at receptor-linked, calcium ion channels (e.g., phencyclidine or MK-801) (Lipton et al. (1994), supra) inhibition via the redox modulatory sites are expected to give only partial inhibition of function and thereby limit unwanted side effects associated with excessive antagonism (Gozlan, supra). At present S-nitrosylation of glutamate receptors by an NO.sup.+ donor (e.g., nitroglycerin) is the only mechanism for partially blocking receptor response in vivo, that would achieve this effect by interaction with the redox modulatory sites (S. A. Lipton et al., Nature (London), 364, 626-632 (1993); S. A. Lipton, Neurochem., 29, 111-114 (1996)).
Thus, a need exists for a method to treat glutamate-related disorders (such as glutamate-related neurodegenerative disorders) with non-toxic glutamate antagonists.
SUMMARY OF THE INVENTION
The present invention provides a therapeutic method comprising preventing or treating a glutamate-related disorder in a mammal, by administering to said mammal an effective amount of a compound of the formula I: ##STR1## wherein a) R.sup.1 and R.sup.2 are individually (C.sub.1 -C.sub.8) alkyl, (C.sub.6 -C.sub.12)aryl, or heteroaryl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are attached are a 4-8 membered ring optionally comprising 1, 2, or 3 additional heteroatoms selected from the group consisting of non-peroxide oxygen, sulfur, and N(R.sub.a), (C.sub.1 -C.sub.8)alkanoyl, phenyl, benzyl, or phenethyl; and R.sup.3 is hydrogen, (C.sub.1 -C.sub.8)alkyl, (C.sub.6 -C.sub.12)aryl, heteroaryl, SC(.dbd.S)N(R.sup.1)(R.sup.2), or a glutathione derivative; or and R.sup.2 is (C.sub.1 -C.sub.8 alkyl, (C.sub.6 -C.sub.12)aryl, or heteroaryl; or attached are an azetidino, pyrrolidino, piperidino, hexamethyleneimin-1-yl, or heptamethylene-imin-1-yl ring, said ring being substituted on carbon by a substituent R.sub.b ; wherein R.sub.b and R
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Faiman Morris
Schloss John V.
Wu Jang-Yen
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