1,4-Methano-2-benzazepine derivatives useful as cerebal dysfunct

Details 1,4-Methano-2-benzazepine derivatives useful as cerebal dysfunct 1,4-Methano-2-benzazepine derivatives useful as cerebal dysfunct

1984-05-07

1985-10-08

Daus, Donald G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548427, A61K 3140, C07D20756

Patent

active

045461074

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD AND DISCLOSURE OF INVENTION

This invention relates to novel and therapeutically useful 1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one derivatives represented by the formula: ##STR2## wherein X is halogen (fluorine, chlorine, bromine or iodine), n is 1 or 2 and R is hydrogen, lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, etc.) or phenyllower alkyl (benzyl, phenethyl, etc.).
Japanese Patent Publication No. 43-22097 (1968), Chem. Pharm. Bull., 14, 324 (1966) and J. Med. Chem., 21, 1105 (1978) mention compounds of the formula: ##STR3## wherein X' is hydrogen or methoxy, which compounds are useful as an intermediate for the synthesis of certain analgesics.
The present inventors have synthesized various compounds having a moiety of 5-membered ring lactam formed by intramolecular ring-closure of gamma-aminobutyric acid (hereinafter abbreviated as GABA) in their structure to investigate their utility. As a result, it has been found that the compounds of the invention have potent antagonistic activities against lethality and convulsions induced by GABA antagonist such as picrotoxin or bicuculline and accordingly, GABA-like activities. GABA per se is considered to be difficult to transmit blood-brain barrier when administered peripherally, so that effects on the central nervous system can be little expected. On the contrary, the compounds of the invention have the aforementioned effects even when orally administered and so are highly useful.
Further, the compounds of the invention have antielectroshock and antimetrazole actions or electrocorticogram-improving action in a temporary cerebral ischemia model, antihypoxia action and the like. Thus, they are also useful as drugs for improving cerebral dysfunction, anticovulsants, antiepileptics, antianxiety drugs, or other medicaments.
On the other hand, the known compounds mentioned above are extremely weak in such actions as compared with the compounds of the invention or practically ineffective in such actions.
The compounds of Formula (I) can be produced by subjecting an oxime compound of the formula: ##STR4## to reducing followed by ring-closure of the resulting product, wherein X and n are the same as defined above, and R.sup.1 is hydrogen or lower alkyl.
The reaction is preferably catalytic reduction, which is carried out in the presence of a metallic catalyst such as Reney nickel, platinum oxide or palladium carbon, in an inert solvent preferably lower alkanol such as methanol or ethanol or lower alkanoic acid such as acetic acid, if desired in the presence of ammonia for the prevention of possible polymerization, at a temperature of from room temperature to 150.degree. C, preferably 50.degree. to 100.degree. C., under an ordinary pressure or 50 to 150 atm of hydrogen. Hydrogen or hydrazine may be used as a source of hydrogen. The reduction can also be carried out by the use of sodium in liquid ammonia containing methanol or by the use of a metal such as zinc or tin and an acid such as hydrochloric acid or acetic acid.
Where the reaction is carried out over about 60.degree. C., there can be obtained the objective compounds of the formula: ##STR5## wherein X and n are the same as defined above, without isolating the intermediate of the formula: ##STR6## wherein X, n and R.sup.1 are the same as defined above.
Otherwise, the intermediate can be isolated and then converted into the compound (Ia) by heating at 60.degree.-200.degree. C.
The compound of Formula (III) in trans-form does not participate in the ring-closure reaction, but can be separated by extraction with an acid or alkali.
The compound of Formula (Ia) is allowed to react with an alkylating agent such as dimethyl sulfate, diethyl sulfate or a compound of the formula: residue such as halogen, methylsulfonyloxy or p-tolylsulfonyloxy, to give the objective products of the formula: ##STR7## wherein X, n and R.sup.2 are the same as defined above.
The reaction is carried out by treating the compound (Ia) with an alkali metal compound such as lithium hydride, sodium hydride, potassi

REFERENCES:
patent: 3474463 (1969-10-01), Schenker
patent: 3890347 (1975-06-01), Middlemiss
Middlemiss, Chem. Abst., vol. 79 (1973) 66171u.
CIBA Ltd., Chem. Abst., vol. 65, 696f.
Faculty of Pharmaceutical Science, Chem. Pharm. Bull. 14(4) 324-329 (1966).
Tadashi Kometani et al., J. M. Chem. 1978, vol. 21, No. 11, 1105-1110.

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