Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-11
1998-08-18
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540557, A61K 3155, C07D24302
Patent
active
057958866
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel dihydro-2,3-benzodiazepine derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as AMPA receptor antagonists.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,835,152, European patent application publication number EP-A1-0492485 and International patent application publication number WO 92/11262 disclose certain dihydro-2,3-benzodiazepine derivatives possessing central nervous system effects, in particular muscle-relaxant and anticonvulsant activity, as well as antidepressive and antiparkinsonian activity. The structure activity relationships of these compounds are discussed in Tarnawa et al; Bioorganic and Medicinal Chemistry; Letters, Vol. 3, No. 1, pp 99-104, 1993.
Compounds having an acetyl, propionyl or N-methylcarbamoyl group at the 3-position of the benzodiazepine ring are reported to be the most potent, and those with a benzoyl or phenylacetyl group amongst the least potent.
Surprisingly, it has been found that certain dihydro-2,3-benzodiazepines having an aromatic group attached directly to the 3-position of the benzodiazepine ring and a p-aminophenyl group attached to the 1-position possess potent anticonvulsant activity.
SUMMARY OF THE INVENTION
The present invention provides a compound having the general formula: ##STR1## wherein R is hydrogen or C.sub.1 -C.sub.10 alkyl;
X is an aromatic moiety selected from phenyl, thienyl, furyl, pyridyl, imidazolyl, benzimidazoyl, benzothiazolyl and phthalazinyl which is unsubstituted or substituted with one or more moietites chosen from the group consisting of halogen, hydroxy, cyano, nitro, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, carboxy, C.sub.1 -C.sub.6 alkoxycarbonyl, acetyl, formyl, carboxymethyl, hydroxymethyl, amino, aminomethyl, methylenedioxy and trifluoromethyl; and
"Aryl" represents p-nitrophenyl, p-aminophenyl or p-(protected amino)phenyl;
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I in which "Aryl" represents p-nitrophenyl or p-(protected amino)phenyl are useful as intermediates in the preparation of compounds of formula I in which "Aryl" represents p-aminophenyl. Certain compounds of formula I in which "Aryl" represents p-(protected amino)phenyl may also be useful as pro-drugs for compounds of formula I in which "Aryl" represents p-aminophenyl.
As used herein, the term "C.sub.1 -C.sub.10 alkyl" represents a straight or branched alkyl chain having from one to ten carbon atoms. Typical straight or branched C.sub.1 -C.sub.10 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, n-octyl, decyl and the like. The term "C.sub.1 -C.sub.10 alkyl" includes within it the terms "C.sub.1 -C.sub.4 alkyl" and "C.sub.1 -C.sub.6 alkyl".
Examples of values for an aromatic moiety represented by x are phenyl, 2-thienyl, 3-thienyl, 2-furyl, 2-pyridyl, 2-imidazolyl, 2-benzimidazolyl, 2-benzothiazolyl and 1-phthalazinyl.
Particular values for substituents which may be present on an aromatic moiety represented by X are fluoro, chloro, bromo, iodo, hydroxy, cyano, nitro, methyl, methoxy, carboxy, methoxycarbonyl, acetyl, formyl, carboxymethyl, hydroxymethyl, amino, aminomethyl and trifluoromethyl.
Examples of values for X are phenyl, 4-methyphenyl, 2-methylphenyl, 4-methoxyphenyl, 4-(i-propyl)phenyl, 4-(t-butyl)phenyl, 4-acetylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-bromophenyl, 3-iodophenyl, 3,4-methylenedioxyphenyl, 2-methoxycarbonylthien-3-yl, 2-pyridyl, 2-benzimidazolyl, 2-benzothiazolyl and 1-phthalazinyl.
"Aryl" used in the formulae throughout the specification represents p-nitrophenyl, p-aminophenyl and p-(protected amino)phenyl such as p-(C.sub.1 -C.sub.6 alkanoylamino)phenyl, for example p-acetylaminophenyl. Examples of suitable protecting groups may be found in McOmie, Protective Groups in Organic Chemistry, Plenum Press, N.Y., 1973, and Gr
REFERENCES:
patent: 5459137 (1995-10-01), Andrasi et al.
Bioorganic & Medical Chemistry Letters, Tarnawa et al., vol. 3, No. 1, pp. 99-104, 1993.
Anderson Benjamin A.
Hansen Marvin M.
Harn Nancy K.
Boone David E.
Eli Lilly and Company
Gupta Yogendra N.
Hay Martin A.
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